Lisinopril formulations

ABSTRACT

Provided herein are stable lisinopril oral liquid formulations. Also provided herein are methods of using lisinopril oral liquid formulations for the treatment of certain diseases including hypertension, heart failure and acute myocardial infarction.

CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.16/564,904 filed on Sep. 9, 2019 which is a continuation of Ser. No.16/295,482, filed Mar. 7, 2019 (now U.S. Pat. No. 10,406,199, issued onSep. 10, 2019), which is a continuation of U.S. patent application Ser.No. 16/053,164, filed Aug. 2, 2018 (now U.S. Pat. No. 10,265,370, issuedon Apr. 23, 2019), which is a continuation of U.S. patent applicationSer. No. 15/805,934, filed Nov. 7, 2017 (now U.S. Pat. No. 10,039,800,issued on Aug. 7, 2018), which is a continuation of U.S. patentapplication Ser. No. 15/483,691, filed Apr. 10, 2017 (now U.S. Pat. No.9,814,751, issued on Nov. 14, 2017), which is a continuation of U.S.patent application Ser. No. 15/268,095, filed Sep. 16, 2016 (now U.S.Pat. No. 9,616,096, issued Apr. 11, 2017), which is a continuation ofU.S. patent application Ser. No. 14/934,752, filed Nov. 6, 2015 (nowU.S. Pat. No. 9,463,183, issued Oct. 11, 2016), which claims the benefitof U.S. Provisional Patent Application No. 62/249,011, filed Oct. 30,2015, all of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

Hypertension, or high blood pressure, is a serious health issue in manycountries. According to the National Heart Blood and Lung Institute, itis thought that about 1 in 3 adults in the United States alone havehypertension. Left unchecked, hypertension is considered a substantialrisk factor for cardiovascular and other diseases including coronaryheart disease, myocardial infarction, congestive heart failure, strokeand kidney failure. Hypertension is classified as primary (essential)hypertension or secondary hypertension. Primary hypertension has noknown cause and may be related to a number of environmental, lifestyleand genetic factors such as stress, obesity, smoking, inactivity andsodium intake. Secondary hypertension can be caused by drug or surgicalinterventions or by abnormalities in the renal, cardiovascular orendocrine system.

A number of antihypertensive drugs are available for treatinghypertension. Various therapeutic classes of antihypertensive drugsinclude alpha-adrenergic blockers, beta-adrenergic blockers,calcium-channel blockers, hypotensives, mineralcorticoid antagonists,central alpha-agonists, diuretics and rennin-angiotensin-aldosteroneinhibitors which include angiotensin II receptor antagonists (ARB) andangiotensin-converting enzyme (ACE) inhibitors. Angiotensin-convertingenzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), apeptydyl dipeptidase that catalyzes angiotension I to angiotension II, apotent vasoconstrictor involved in regulating blood pressure.

Lisinopril is a drug belonging to the angiotensin-converting enzyme(ACE) inhibitor class of medications. Lisinopril IUPAC name isN²-[(1S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline. Its structuralformula is as follows:

Lisinopril is currently administered in the form of oral tablets, (e.g.,Prinivil®, Zestril®). In addition to the treatment of hypertension,lisinopril tablets have been used for the treatment of heart failure andacute myocardial infarction.

SUMMARY OF THE INVENTION

Provided herein are lisinopril oral liquid formulations. In one aspect,the lisinopril oral liquid formulation comprises (i) lisinopril or apharmaceutically acceptable salt or solvate thereof, (ii) a sweetenerthat is xylitol, (iii) a buffer comprising citric acid (iv) apreservative that is sodium benzoate, and (v) water; wherein the pH ofthe formulation is between about 4 and about 5; and wherein theformulation is stable at about 25±5° C. for at least 12 months.

In some embodiments, the lisinopril is lisinopril dihydrate. In someembodiments, the formulation further comprises a flavoring agent. Insome embodiments, the formulation further comprises a second sweetener.In some embodiments, the second sweetener is sodium saccharin orsucralose. In some embodiments, the pH is about 4.9. In someembodiments, the formulation is stable at about 25±5° C. for at least 18months. In some embodiments, the formulation is stable at about 25±5° C.for at least 24 months. In some embodiments, the buffer furthercomprises sodium citrate.

In some embodiments, the amount of lisinopril or a pharmaceuticallyacceptable salt or solvate thereof is about 0.8 to about 1.2 mg/ml. Insome embodiments, the amount of xylitol is about 140 to about 160 mg/ml.In some embodiments, the amount of citric acid in the buffer is about0.5 to about 1.2 mg/ml. In some embodiments, the amount of sodiumcitrate in the buffer is about 1.2 to about 1.7 mg/ml. In someembodiments, the amount of the sodium benzoate is about 0.5 to about 1.2mg/ml.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol,(iii) a buffer comprising about 0.86 mg/ml citric acid, (iv) about 0.8mg/ml of a preservative that is sodium benzoate; and (v) water; whereinthe pH of the formulation is between about 4 and about 5; and whereinthe formulation is stable at about 25±5° C. for at least 12 months.

In some embodiments, the lisinopril is lisinopril dihydrate. In someembodiments, the formulation further comprises a flavoring agent. Insome embodiments, the formulation further comprises a second sweetener.In some embodiments, the second sweetener is sodium saccharin orsucralose. In some embodiments, the pH is about 4.9. In someembodiments, the formulation is stable at about 25±5° C. for at least 18months. In some embodiments, the formulation is stable at about 25±5° C.for at least 24 months. In some embodiments, the buffer furthercomprises sodium citrate. In some embodiments, the buffer furthercomprises about 1.44 mg/ml sodium citrate.

In some embodiments, the amount of lisinopril or a pharmaceuticallyacceptable salt or solvate thereof is about 0.5 to about 1 (w/w ofsolids). In some embodiments, the amount of xylitol is about 95 to about98% (w/w of solids). In some embodiments, the amount of citric acid inthe buffer is about 0.3 to about 0.7% (w/w of solids). In someembodiments, the amount of sodium citrate in the buffer is about 0.7 toabout 1.3% (w/w of solids). In some embodiments, the amount of sodiumbenzoate is about 0.4 to about 1.2% (w/w of solids).

In another aspect, the lisinopril oral liquid formulation comprises (i)about 0.7% (w/w of solids) lisinopril or a pharmaceutically acceptablesalt or solvate thereof, (ii) about 97.3% (w/w of solids) of a sweetenerthat is xylitol, (iii) a buffer comprising about 0.01 molar citrate,(iv) about 0.52% (w/w of solids) of a preservative that is sodiumbenzoate, and (v) water; wherein the pH of the formulation is betweenabout 4 and about 5; and wherein the formulation is stable at about25±5° C. for at least 12 months.

In some embodiments, the lisinopril is lisinopril dihydrate. In someembodiments, the formulation further comprises a flavoring agent. Insome embodiments, the formulation further comprises a second sweetener.In some embodiments, the second sweetener is sodium saccharin orsucralose. In some embodiments, the pH is about 4.9. In someembodiments, the formulation is stable at about 25±5° C. for at least 18months. In some embodiments, the formulation is stable at about 25±5° C.for at least 24 months. In some embodiments, the buffer comprises citricacid and sodium citrate.

In another aspect, the lisinopril oral liquid formulation consists of(i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol,(iii) a buffer comprising about 0.86 mg/ml citric acid and about 1.44mg/ml sodium citrate, (iv) about 0.8 mg/ml of a preservative that issodium benzoate, (v) and water; wherein the pH of the formulation isbetween about 4 and about 5 adjusted by sodium hydroxide or hydrochloricacid; and wherein the formulation is stable at about 25±5° C. for atleast 12 months. In some embodiments, the formulation is stable at about25±5° C. for at least 24 months. In some embodiments, the pH is about4.9.

Also provided herein are methods of treating hypertension comprisingadministering to a patient in need thereof a lisinopril oral liquidformulation described herein. In some embodiments, the hypertension isprimary (essential) hypertension. In some embodiments, the hypertensionis secondary hypertension, in some embodiments, the subject withhypertension has blood pressure values greater than or equal to 140/90mm Hg.

Also provided herein are methods of treating prehypertension comprisingadministering to a patient in need thereof a lisinopril oral liquidformulation described herein. In some embodiments, the subject withprehypertension has blood pressure values of about 120-139/80-89 mm Hg,

Also provided herein are methods of treating heart failure or acutemyocardial infarction comprising administering to a patient in needthereof a lisinopril oral liquid formulation described herein.

In some embodiments, the subject is an adult. In some embodiments, thesubject is elderly. In some embodiments, the subject is a child. In someembodiments, the lisinopril oral liquid formulation is administered tothe subject in a fasted state. In some embodiments, the lisinopril oralliquid formulation is administered to the subject in a fed state.

in some embodiments, the lisinopril oral liquid formulation is furtheradministered in combination with an agent selected from the groupconsisting of diuretics, beta blockers, alpha blockers, mixed alpha andbeta blockers, calcium channel blockers, angiotensin II receptorantagonists, ACE inhibitors, aldosterone antagonists, and alpha-2agonists.

Also provided herein is a process for preparing a stable oral liquidformulation comprising lisinopril, xylitol, a buffer, and sodiumbenzoate, the process which comprises the step of adding about 0.86mg/ml anhydrous citric acid, about 1.44 mg/ml anhydrous sodium citrate,about 0.80 mg/ml sodium benzoate, about 1.09 mg/ml lisinopril dihydrate,and about 150 mg/ml xylitol to water; adjusting the volume to thedesired volume by adding more water; and adjusting the pH to 4.9 byadding sodium hydroxide or hydrochloric acid.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1: Degradant formation in lisinopril formulations after 145 hoursat 60° C. (Δ-Lisinopril diketopiperazine, □-hydrolysate).

FIG. 2: Chromatograms showing esterification degradation peaks informulation 1 (containing lisinopril, parabens and xylitol) and placebo1 (containing parabens and xylitol) versus formulation 2 (containinglisinopril and paraben but no sugar alcohol) and placebo 2 (containingparaben but no sugar alcohol).

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are stable lisinopril oral liquid formulations. Alsoprovided herein are stable lisinopril powder formulations forreconstitution for oral liquid administration. These lisinoprilformulations described herein are useful for the treatment ofhypertension, prehypertension, heart failure as well as acute myocardialinfarction. The formulations are advantageous over conventional soliddosage administration of lisinopril ranging from ease of administration,accuracy of dosing, accessibility to additional patient populations suchas to children and the elderly, and an increased patient compliance tomedication.

It is generally known that certain segments of the population havedifficulty ingesting and swallowing solid oral dosage forms such astablets and capsules. As many as a quarter of the total population hasthis difficulty. Often, this leads to non-compliance with therecommended medical therapy with the solid dosage forms, therebyresulting in rending the therapy ineffective. Further, solid dosageforms are not recommended for children or elderly due to increased riskin choking.

Furthermore, the dose of lisinopril to be given to children iscalculated according to the child's weight. When the calculated dose issomething other than the amount present in one or more intact soliddosage forms, the solid dosage form must be divided to provide thecorrect dose. This leads to inaccurate dosing when solid dosages forms,such as tablets, are compounded to prepare other formulations forchildren.

For lisinopril, the current solution to overcoming the use of the tabletform is for a compounding pharmacist to pulverize and crush thelisinopril tablet(s) into a powder via mortar and pestle andreconstitute the powder in some liquid form. However forming alisinopril oral liquid in this fashion has significant drawbacksincluding large variability in the actual dosage, incompletesolubilizing of the lisinopril tablet in the liquid, rapid instability,inconsistent formulation methods per compounding pharmacy, and a numberof other potential issues. The crushed tablet liquid formulation mayalso be potentially unsafe due to contamination with residual drugs andother substances from the mortar and pestle or other crushing agent.

The present embodiments provide a safe and effective oral administrationof lisinopril for the treatment of hypertension and other disorders. Inparticular, the embodiments provide stable lisinopril oral liquidformulations as well as lisinopril powder formulations forreconstitution for oral liquid administration.

As used herein, “lisinopril” refers to lisinopril base, its salt, orsolvate or derivative or isomer or polymorph thereof. Suitable compoundsinclude the free base, the organic and inorganic salts, isomers, isomersalts, solvates, polymorphs, complexes etc. U.S. Pat. Nos. 4,374,829,4,472,380, and CA 1,275,350 disclose exemplary methods in thepreparation of lisinopril. In some embodiments, the lisinopril used inthe formulations described herein is a lisinopril salt. In someinstances, the lisinopril used in the formulations described herein is alisinopril hydrate. In some instances, the lisinopril used in theformulations described herein is lisinopril monohydrate. In someinstances, the lisinopril used in the formulations described herein islisinopril dihydrate.

Other ACE inhibitors are contemplated in the formulations within andinclude but are not limited to quinapril, indolapril, ramipril,perindopril, benazepril, imidapril, zofenopril, trandolapril,fosinopril, captopril, and their salts, solvates, derivatives,polymorphs, complexes, thereof.

Lisinopril Oral Liquid Formulations

Oral liquids include, but are not limited to, solutions (both aqueousand nonaqueous), suspensions, emulsions, syrups, slurries, juices,elixirs, dispersions, and the like. It is envisioned thatsolution/suspensions are also included where certain componentsdescribed herein are in a solution while other components are in asuspension.

In one aspect, the lisinopril oral liquid formulation described hereincomprise lisinopril, a preservative, a sweetening agent, a buffer, andwater. In one embodiment, the sweetening agent is xylitol. In someembodiments, the sweetening agent is sucralose. In some embodiments, thesweetener is saccharin. In another embodiment, the preservative issodium benzoate. In yet another embodiment, the preservative is one ormore paraben preservatives. In yet another embodiment, the buffercomprises citric acid. In yet another embodiment, the buffer comprisescitric acid and sodium citrate. In yet another embodiment, the buffercomprises phosphoric acid or salts thereof. In one aspect, thelisinopril oral liquid formulation described herein compriseslisinopril, xylitol, sodium citrate, citric acid, sodium benzoate, andwater. In some embodiments, the lisinopril oral liquid formulationherein further comprises a flavoring agent.

In some embodiments, lisinopril is present in about 0.8 mg/ml to about1.2 mg/ml in the oral liquid formulation. In other embodiments,lisinopril is present in about 0.8 mg/ml, 0.81 mg/ml, about 0.82 mg/ml,about 0.83 mg/ml, about 0.84 mg/ml, about 0.85 mg/ml, about 0.86 mg/ml,about 0.87 mg/ml, about 0.88 mg/ml, about 0.89 mg/ml, about 0.9 mg/ml,about 0.91 mg/ml, about 0.92 mg/ml, about 0.93 mg/ml, about 0.94 mg/ml,about 0.95 mg/ml, about 0.96 mg/ml, about 0.97 mg/ml, about 0.98 mg/ml,about 0.99 mg/ml, about 1 mg/ml, about 1.01 mg/ml, about 1.02, mg/ml,about 1.03 mg/ml, about 1.04 mg/ml, about 1.05 mg/ml, about 1.06 mg/ml,about 1.07 mg/ml, about 1.08 mg/ml, about 1.09 mg/ml, about 1.1 mg/ml,about 1.11 mg/ml, about 1.12, mg/ml, about 1.13 mg/ml, about 1.14 mg/ml,about 1.15 mg/ml, about 1.16 mg/ml, about 1.17 mg/ml, about 1.18 mg/ml,about 1.19 mg/ml, or about 1.2 mg/ml in the liquid oral formulation. Insome embodiments, lisinopril is present in about 1 mg/ml in the oralliquid formulation.

In some embodiments, lisinopril is present in about 0.5% w/w to about 5%w/w of the solids in the oral liquid formulation. In other embodiments,Lisinopril is present in about 0.5 w/w, about 0.55% w/w, about 0.6% w/w,about 0.65% w/w, about 0.7% w/w, about 0.75% w/w, about 0.8% w/w, about0.85% w/w, about 0.9% w/w, about 0.95% w/w, about 1% w/w, about 1.1%w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w,about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2%w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w,about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about2.9% w/w, about 3% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w,about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about3.8% w/w, about 3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w,about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6% w/w, about4.7% w/w, about 4.8% w/w, about 4.9% w/w, or about 5% w/w of the solidsin the oral liquid formulation. In some embodiments, lisinopril ispresent in about 0.5 w/w to about 1 w/w of the solids in the oral liquidformulation. In some embodiments, lisinopril is present in about 0.6%w/w to about 0.8% w/w of the solids in the oral liquid formulation. Insome embodiments, lisinopril is present in about 0.7% w/w of the solidsin the oral liquid formulation.

In some embodiments, lisinopril is present in about 10% w/w to about 25%w/w of the solids in the oral liquid formulation. In other embodiments,lisinopril is present in about 10% w/w, about 10.5% w/w, about 11% w/w,about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5%w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w,about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, about20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w,about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about24.5% w/w, or about 25% w/w of the solids in the oral liquidformulation. In some embodiments, lisinopril is present in about 14% w/wto about 16% w/w of the solids in the oral liquid formulation. In someembodiments, lisinopril is present in about 17% w/w to about 19% w/w ofthe solids in the oral liquid formulation. In some embodiments,lisinopril is present in about 20% w/w to about 22% w/w of the solids inthe oral liquid formulation.

Sweetener in the Lisinopril Oral Liquid Formulations

Sweeteners or sweetening agents include any compounds that provide asweet taste. This includes natural and synthetic sugars, natural andartificial sweeteners, natural extracts and any material that initiatesa sweet sensation in a subject. In some embodiments, a solid/powdersweetener is used in the oral liquid formulation described herein. Inother embodiments, a liquid sweetener is used in the oral liquidformulation described herein.

Sugars illustratively include glucose, fructose, sucrose, xylitol,tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenatedisomaltulose), lactitol, sorbitol, erythritol, trehalose, maltodextrin,polydextrose, and the like. Other sweeteners illustratively includeglycerin, inulin, erythritol, maltol, acesulfame and salts thereof,e.g., acesulfame potassium, alitame, aspartame, neotame, sodiumcyclamate, saccharin and salts thereof, e.g., saccharin sodium orsaccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin,and the like. Sweeteners can be used in the form of crude or refinedproducts such as hydrogenated starch hydrolysates, maltitol syrup, highfructose corn syrup, etc., and as branded products, e.g., Sweet Am™liquid (Product Code 918.003-propylene glycol, ethyl alcohol, andproprietary artificial flavor combination, Flavors of North America) andSweet Am™ powder (Product Code 918.005—maltodextrin, sorbitol, andfructose combination and Product Code 918.010—water, propylene glycol,sorbitol, fructose, and proprietary natural and artificial flavorcombination, Flavors of North America), ProSweet™ (1-10% proprietaryplant/vegetable extract and 90-99% dextrose combination, ViriginiaDare), Maltisweet™ (maltitol solution, Ingredion), Sorbo™ (sorbitol andsorbitol/xylitol solution, SPI Polyols), Invertose™ (high fructose cornsyrup, Ingredion), Rebalance M60 and X60 (sucralose and maltodextrin,Tate and Lyle), and Ora-Sweet® sugar-free flavored syrup (PaddockLaboratories, Inc.). Sweeteners can be used singly or in combinations oftwo or more. Suitable concentrations of different sweeteners can beselected based on published information, manufacturers' data sheets andby routine testing.

In some embodiments, the lisinopril oral liquid formulation describedherein comprises a sweetening agent. In some embodiments, the sweeteningagent is sucralose. In some embodiments, the sweetening agent isxylitol. In some embodiments, the sweetener is saccharin.

In some embodiments, the sweetening agent is xylitol. In someembodiments, xylitol is present in about 140 mg/ml to about 160 mg/ml inthe oral liquid formulation. In other embodiments, xylitol is present inabout 140 mg/ml, about 141 mg/ml, about, 142 mg/ml, about 143 mg/ml,about 144 mg/ml, about 145 mg/ml, about 146 mg/ml, about 147 mg/ml,about 148 mg/ml, about 149 mg/ml, about 150 mg/ml, about 151 mg/ml,about 152 mg/ml, about 153 mg/ml, about 154 mg/ml, about 155 mg/ml,about 156 mg/ml, about 157 mg/ml, about 158 mg/ml, about 159 mg/ml, orabout 160 mg/ml in the oral liquid formulation. In some embodiments,xylitol is present in about 150 mg/ml in the oral liquid formulation.

In some embodiments, xylitol is present in about 80% w/w to about 99%w/w of the solids in the oral liquid formulation. In other embodiments,xylitol is present in about 80% w/w, about 81% w/w, about 82% w/w, about83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about 87% w/w,about 88% w/w, about 89% w/w, about 90% w/w, about 91% w/w, about 92%w/w, about 93% w/w, about 94% w/w, about 95% w/w, about 96% w/w, about97% w/w, about 98% w/w, about 99% w/w of the solids in the oral liquidformulation. In some embodiments, xylitol is present in about 96% w/w toabout 98% w/w of the solids in the oral liquid formulation. In someembodiments, xylitol is present in about 97% w/w of the solids in theoral liquid formulation.

In some embodiments, the sweetening agent is sucralose. In someembodiments, sucralose is present in about 0.5 mg/ml to about 3 mg/ml inthe oral liquid formulation. In other embodiments, sucralose is presentin about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml,about 0.9 mg/ml, about 1 mg/ml, about 1.1 mg/ml, about, 1.2 mg/ml, about1.3 mg/ml, about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7mg/ml, about 1.8 mg/ml, about 1.9 mg/ml, about 2 mg/ml, about 2.1 mg/ml,about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml,about 2.6 mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, orabout 3 mg/ml in the oral liquid formulation. In some embodiments,sucralose is present in about 2 mg/ml in the oral liquid formulation. Insome embodiments, sucralose is present in about 0.7 mg/mL in the oralliquid formulation.

In some embodiments, sucralose is present in about 10% w/w to about 40%w/w of the solids in the oral liquid formulation. In other embodiments,sucralose is present in about 10% w/w, about 10.5% w/w, about 11% w/w,about 11.5% w/w, about 12% w/w, about 12.5% w/w, about 13% w/w, about13.5% w/w, about 14% w/w, about 14.5% w/w, about 15% w/w, about 15.5%w/w, about 16% w/w, about 16.5% w/w, about 17% w/w, about 17.5% w/w,about 18% w/w, about 18.5% w/w, about 19% w/w, about 19.5% w/w, about20% w/w, about 20.5% w/w, about 21% w/w, about 21.5% w/w, about 22% w/w,about 22.5% w/w, about 23% w/w, about 23.5% w/w, about 24% w/w, about24.5% w/w, about 25% w/w, about 25.5% w/w, about 26% w/w, about 26.5%w/w, about 27% w/w, about 27.5% w/w, about 28% w/w, about 28.5% w/w,about 29% w/w, about 29.5% w/w, about 30% w/w, about 30.5% w/w, about31% w/w, about 31.5% w/w, about 32% w/w, about 32.5% w/w, about 33% w/w,about 33.5% w/w, about 34% w/w, about 34.5% w/w, about 35% w/w, about35.5% w/w, about 36% w/w, about 36.5% w/w, about 37% w/w, about 37.5%w/w, about 38% w/w, about 38.5% w/w, about 39% w/w, about 39.5% w/w, orabout 40% w/w of the solids in the oral liquid formulation. In someembodiments, sucralose is present in about 34% w/w to about 35 w/w ofthe solids in the oral liquid formulation. In some embodiments,sucralose is present in about 28% w/w to about 30% w/w of the solids inthe oral liquid formulation. In some embodiments, sucralose is presentin about 12% w/w to about 15% w/w of the solids in the oral liquidformulation.

In some embodiments, the sweetening agent is saccharin. In someembodiments, saccharin is present in about 1 mg/ml to about 3 mg/ml inthe oral liquid formulation. In other embodiments, saccharin is presentin about 1 mg/ml, about 1.1 mg/ml, about, 1.2 mg/ml, about 1.3 mg/ml,about 1.4 mg/ml, about 1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml,about 1.8 mg/ml, about 1.9 mg/ml, about 2 mg/ml, about 2.1 mg/ml, about2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6mg/ml, about 2.7 mg/ml, about 2.8 mg/ml, about 2.9 mg/ml, or about 3mg/ml in the oral liquid formulation. In some embodiments, saccharin ispresent in about 2 mg/ml in the oral liquid formulation.

In some embodiments, saccharin is present in about 1% w/w to about 3%w/w of the solids in the oral liquid formulation. In other embodiments,saccharin is present in about 1 w/w, 1.1% w/w, about 1.2% w/w, 1.3% w/w,about 1.4% w/w, 1.5% w/w, about 1.6% w/w, 1.7% w/w, about 1.8% w/w, 1.9%w/w, about 2% w/w, 2.1% w/w, about 2.2% w/w, 2.3% w/w, about 2.4% w/w,2.5% w/w, about 2.6% w/w, 2.7% w/w, about 2.8% w/w, 2.9% w/w, or 3% w/wof the solids in the oral liquid formulation. In some embodiments,saccharin is present in about 1.7% w/w to about 1.9% w/w of the solidsin the oral liquid formulation.

Preservative in the Lisinopril Oral Liquid Formulations

Preservatives include anti-microbials, anti-oxidants, and agents thatenhance sterility. Exemplary preservatives include ascorbic acid,ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaricacid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate,sodium metabisulfite, sodium sulfite, parabens (such as methylparaben,ethylparaben, propylparaben, butylparaben and their salts), benzoicacid, sodium benzoate, potassium sorbate, vanillin, and the like.

In some embodiments, the lisinopril oral liquid formulation describedherein comprises a preservative.

In some embodiments, the preservative is a paraben and the sweetener isnot a sugar (such as, but not limited to glucose, fructose, sucrose,lactose, maltose) or a sugar alcohol (such as, but not limited toxylitol, mannitol, lactitol, maltitol, sorbitol).

In some embodiments, the preservative is sodium benzoate.

In some embodiments, modulation of the pH is desired to provide the bestantimicrobial activity of the preservative, sodium benzoate. In someembodiments, the antimicrobial activity of sodium benzoate drops whenthe pH is increased above 5.

In some embodiments, the pH of the lisinopril oral liquid formulationdescribed herein is less than about 5.1. In some embodiments, the pH ofthe lisinopril oral liquid formulation described herein is less thanabout 5. In some embodiments, the pH of the lisinopril oral liquidformulation described herein is between about 4 and about 5. In someembodiments, the pH of the lisinopril oral liquid formulation describedherein is about 4, about 4.1, about 4.2, about 4.3, about 4.4, about4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, orabout 5.2.

In some embodiments, sodium benzoate is present in about 0.5 mg/ml toabout 1.2 mg/ml in the oral liquid formulation. In other embodiments,sodium benzoate is present in about 0.5 mg/ml, about 0.55 mg/ml, about0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1mg/ml, about 1.05 mg/ml, about 1.1 mg/ml, about 1.15 mg/ml, or about 1.2mg/ml in the liquid oral formulation. In some embodiments, sodiumbenzoate is present in about 0.8 mg/ml in the oral liquid formulation.

In some embodiments, sodium benzoate is present in about 0.1% w/w toabout 5% w/w of the powder formulation. In other embodiments, sodiumbenzoate is present in about 0.1% w/w, about 0.15% w/w, about 0.2% w/w,about 0.25% w/w, about 0.30% w/w, about 0.35% w/w, about 0.40% w/w,about 0.45% w/w, about 0.50% w/w, about 0.55% w/w, about 0.60% w/w,about 0.65% w/w, about 0.70% w/w, about 0.75% w/w, about 0.80% w/w,about 0.85% w/w, about 0.90% w/w, about 0.95% w/w, about 1% w/w, about1.5% w/w, about 2% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w,about 4.5% w/w, or about 5% w/w of the powder formulation. In someembodiments, sodium benzoate is present in about 0.4% w/w to about 1.2%w/w of the powder formulation. In some embodiments, sodium benzoate ispresent in about 0.52% w/w of the powder formulation.

In some embodiments, sodium benzoate is present in about 10% w/w toabout 17% w/w of the solids in the oral liquid formulation. In otherembodiments, sodium benzoate is present in about 10% w/w, about 10.5%w/w, about 11% w/w, about 11.5% w/w, about 12% w/w, about 12.5% w/w,about 13% w/w, about 13.5% w/w, about 14% w/w, about 14.5% w/w, about15% w/w, about 15.5% w/w, about 16% w/w, about 16.5% w/w, or about 17%w/w of the solids in the oral liquid formulation. In some embodiments,sodium benzoate is present in about 12% w/w to about 17% w/w of thesolids in the oral liquid formulation.

In some embodiments, sodium benzoate is present in an amount sufficientto provide antimicrobial effectiveness to the lisinopril oral liquidformulation described herein (see table D−1)

In some embodiments, the preservative is a paraben. In some embodiments,the preservative is a mixture of parabens. In some embodiments, theparaben or mixture of parabens is present in about 0.1 mg/ml to about 2mg/ml in the oral liquid formulation. In other embodiments, the parabenor mixture of parabens is present in about 0.1 mg/ml, about 0.2 mg/ml,about 0.3 mg/ml, about 0.4 mg/ml, about 0.5 mg/ml, about 0.6 mg/ml,about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 1 mg/ml, about1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml, or about1.5 mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 1.9mg/ml, or about 2 mg/ml in the liquid oral formulation. In someembodiments, the paraben or mixture of parabens is present in about 1.6mg/ml to about 2 mg/ml in the oral liquid formulation. In someembodiments, the paraben or mixture of parabens is present in about 1.6mg/ml to about 1.8 mg/ml in the oral liquid formulation. In someembodiments, the paraben or mixture of parabens is present in about 0.1mg/ml to about 0.2 mg/ml in the oral liquid formulation.

In some embodiments, the paraben or mixture of parabens is present inabout 2% w/w to about 30% w/w of the solids in the oral liquidformulation. In other embodiments, the paraben or mixture of parabens ispresent in about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w,about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20%w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, orabout 30% w/w of the solids in the oral liquid formulation. In someembodiments, the paraben or mixture of parabens is present in about 2%w/w to about 3% w/w of the solids in the oral liquid formulation. Insome embodiments, the paraben or mixture of parabens is present in about23% w/w to about 26% w/w of the solids in the oral liquid formulation.In some embodiments, the paraben or mixture of parabens is present inabout 26% w/w to about 30% w/w of the solids in the oral liquidformulation.

Sweetener and Preservative Incompatibility

As shown in the examples and in FIG. 2, paraben preservatives(especially methylparaben) can react with selected sugars (glucose,fructose, sucrose, lactose, maltose) and sugar alcohols (xylitol,mannitol, lactitol, maltitol, sorbitol) to form transesterificationreaction products. This can be undesirable from a formulation andstability standpoint as the transesterification creates additionaldegradants.

In some embodiments, the lisinopril oral liquid formulation describedherein does not comprise a paraben preservative. In further embodiments,the lisinopril oral liquid formulation described herein does notcomprise a paraben preservative when the formulation also comprises asugar or sugar alcohol.

pH of Lisinopril Oral Liquid Formulations

Buffering agents maintain the pH of the lisinopril oral liquidformulation described herein. Non-limiting examples of buffering agentsinclude, but are not limited to sodium bicarbonate, potassiumbicarbonate, magnesium hydroxide, magnesium lactate, magnesiumglucomate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonateco-precipitate, mixture of an amino acid and a buffer, a mixture ofaluminum glycinate and a buffer, a mixture of an acid salt of an aminoacid and a buffer, and a mixture of an alkali salt of an amino acid anda buffer. Additional buffering agents include citric acid, sodiumcitrate, sodium tartrate, sodium acetate, sodium carbonate, sodiumpolyphosphate, potassium polyphosphate, sodium pyrophosphate, potassiumpyrophosphate, disodium hydrogenphosphate, dipotassiumhydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodiumacetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide,magnesium carbonate, magnesium silicate, calcium acetate, calciumglycerophosphate, calcium chloride, calcium hydroxide, calcium lactate,calcium carbonate, calcium bicarbonate, and other calcium salts. Somebuffering agents also impart effervescent qualities when a powder isreconstituted in a solution.

In some embodiments, the lisinopril oral liquid formulation describedherein comprises a buffer.

In some embodiments, the buffer in the lisinopril oral liquidformulation described herein comprises citric acid. In some embodiments,the buffer in the lisinopril oral liquid formulation described hereincomprises citric acid and sodium citrate.

In some embodiments, the buffer in the lisinopril oral liquidformulation described herein comprises phosphoric acid. In someembodiments, the buffer in the lisinopril oral liquid formulationdescribed herein comprises sodium phosphate.

In some embodiments, the buffer concentration is between about 5 mM andabout 50 mM. In some embodiments, the buffer concentration is betweenabout 5 mM and about 20 mM. In some embodiments, the bufferconcentration is about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM,about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, orabout 20 mM. In some embodiments, the buffer concentration is about 5mM. In some embodiments, the buffer concentration is about 10 mM. Insome embodiments, the buffer concentration is about 20 mM.

In some embodiments, modulation of the pH is desired to provide thelowest impurity profile. In the exemplary stability studies, the mainlisinopril degradants are lisinopril diketopiperazine (also known as:Related Compound A) and lisinopril hydrolysate:

In some embodiments, the percentage of lisinopril diketopiperazine(Related Compound A) and lisinopril hydrolysate formation is increasedwhen the pH is below 4. (See tables A-2, B-2, C-2, F-2, and FIG. 1).

In some embodiments, the pH of the lisinopril oral liquid formulationdescribed herein is less than about 4. In some embodiments, the pH ofthe lisinopril oral liquid formulation described herein is more thanabout 5. In some embodiments, the pH of the lisinopril oral liquidformulation described herein is between about 4 and about 5. In someembodiments, the pH of the lisinopril oral liquid formulation describedherein is about 4, about 4.1, about 4.2, about 4.3, about 4.4, about4.5, about 4.6, about 4.7, about 4.8, about 4.9, or about 5. In someembodiments, the pH of the lisinopril oral liquid formulation describedherein is between about 5 and about 8.

In some embodiments, citric acid is present in about 0.50 mg/ml to about5.5 mg/ml in the oral liquid formulation. In other embodiments, citricacid is present in about 0.50 mg/ml to about 2 mg/mL in the oral liquidformulation. In other embodiments, citric acid is present in about 0.50mg/ml, about 0.55 mg/ml, about 0.60 mg/ml, about 0.65 mg/ml, about 0.70mg/ml, about 0.75 mg/ml, about 0.80 mg/ml, about 0.85 mg/ml, about 0.90mg/ml, about 0.95 mg/ml, about 1.0 mg/ml, about 1.05 mg/ml, about 1.1mg/ml, about 1.15 mg/ml, about 1.2 mg/ml, 1.25 mg/ml, about 1.30 mg/ml,about 1.35 mg/ml, about 1.4 mg/ml, about 1.45 mg/ml, about 1.5 mg/ml,about 1.55 mg/ml, about 1.6 mg/ml, about 1.65 mg/ml, about 1.7 mg/ml,about 1.75 mg/ml, about 1.80 mg/ml, about 1.85 mg/ml, about 1.9 mg/ml,about 1.95 mg/ml, or about 2 mg/ml in the oral liquid formulation. Insome embodiments, citric acid is present in about 0.86 mg/ml in the oralliquid formulation. In some embodiments, citric acid is present in about1.92 mg/ml in the oral liquid formulation. In some embodiments, citricacid is present in about 5.5 mg/ml in the oral liquid formulation.

In some embodiments, citric acid is present in about 0.1% w/w to about5% w/w of the solids in the oral liquid formulation. In otherembodiments, citric acid is present in about 0.10% w/w, about 0.15% w/w,about 0.20% w/w, about 0.25% w/w, about 0.30% w/w, about 0.35% w/w,about 0.40% w/w, about 0.45% w/w, about 0.50% w/w, about 0.55% w/w,about 0.60% w/w, about 0.65% w/w, about 0.70% w/w, about 0.75% w/w,about 0.80% w/w, about 0.85% w/w, about 0.90% w/w, about 0.95% w/w,about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3%w/w, about 3.5% w/w, about 4% w/w, about 4.5 w/w, or about 5% w/w of thesolids in the oral liquid formulation. In some embodiments, citric acidis present in about 0.55 w/w the solids in the oral liquid formulation.

In some embodiments, citric acid is present in about 15% w/w to about35% w/w of the powder formulation. In other embodiments, citric acid ispresent in about 15 w/w, about 15.5 w/w, about 16% w/w, about 16.5% w/w,about 17% w/w, about 17.5% w/w, about 18% w/w, about 18.5% w/w, about19% w/w, about 19.5% w/w, about 20% w/w, about 20.5% w/w, about 21% w/w,about 21.5% w/w, about 22% w/w, about 22.5% w/w, about 23% w/w, about23.5% w/w, about 24% w/w, about 24.5% w/w, about 25% w/w, about 25.5%w/w, about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w,about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, about30% w/w, about 30.5% w/w, about 31% w/w, about 31.5% w/w, about 32% w/w,about 32.5% w/w, about 33% w/w, about 33.5% w/w, about 34% w/w, about34.5% w/w, or about 35% w/w of the solids in the oral liquidformulation. In some embodiments, citric acid is present in about 0.55w/w the solids in the oral liquid formulation.

In some embodiments, sodium citrate is present in about 1.2 mg/ml toabout 8.8 mg/ml in the oral liquid formulation. In other embodiments,sodium citrate is present in about 1.2 mg/ml to about 1.7 mg/mL in theoral liquid formulation. In other embodiments, sodium citrate is presentin about 1.2 mg/ml, about 1.25 mg/ml, about 1.30 mg/ml, about 1.35mg/ml, about 1.40 mg/ml, about 1.45 mg/ml, about 1.50 mg/ml, about 1.55mg/ml, about 1.60 mg/ml, about 1.65 mg/ml, or about 1.7 mg/ml in theoral liquid formulation. In some embodiments, sodium citrate is presentin about 1.44 mg/ml in the oral liquid formulation. In some embodiments,sodium citrate is present in about 8.8 mg/ml in the oral liquidformulation.

In some embodiments, sodium citrate is present in about 0.1% w/w toabout 5% w/w of the solids in the oral liquid formulation. In otherembodiments, citric acid is present in about 0.10% w/w, about 0.15% w/w,about 0.20% w/w, about 0.25% w/w, about 0.30% w/w, about 0.35% w/w,about 0.40% w/w, about 0.45 w/w, about 0.50 w/w, about 0.55% w/w, about0.60% w/w, about 0.65% w/w, about 0.70% w/w, about 0.75% w/w, about0.80% w/w, about 0.85% w/w, about 0.90% w/w, about 0.95% w/w, about 1%w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about3.5 w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w of the solids inthe oral liquid formulation. In some embodiments, sodium citrate ispresent in about 0.93% w/w of the solids in the oral liquid formulation.

In other embodiments, sodium citrate is present in about 25% w/w toabout 35% w/w of the solids in the oral liquid formulation. In otherembodiments, citric acid is present in about 25% w/w, about 25.5% w/w,about 26% w/w, about 26.5% w/w, about 27% w/w, about 27.5% w/w, about28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w, or about 30%w/w, about 30.5% w/w, about 31% w/w, about 31.5% w/w, about 32% w/w,about 32.5% w/w, about 33% w/w, about 33.5% w/w, about 34% w/w, about34.5% w/w, or about 35% w/w of the solids in the oral liquidformulation. In some embodiments, sodium citrate is present in about 30%w/w of the solids in the oral liquid formulation.

In other embodiments, sodium citrate is not added to the formulation.

Additional Excipients

In further embodiments, the lisinopril oral liquid formulation describedherein comprises additional excipients including, but not limited to,glidants, flavoring agents, coloring agents and thickeners. Additionalexcipients such as bulking agents, tonicity agents and chelating agentsare within the scope of the embodiments.

Glidants are substances that improve flowability of a powder. Suitableglidants include, but are not limited to, calcium phosphate tribasic,calcium silicate, cellulose (powdered), colloidal silicon dioxide,magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talcand the like. In some embodiments, the lisinopril powder formulationsdescribed herein comprise a glidant.

In another embodiment, the lisinopril oral liquid formulation describedherein comprises a flavoring agent or flavorant to enhance the taste oraroma of the formulation in liquid form. Suitable natural or syntheticflavoring agents can be selected from standard reference books, forexample Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).Non-limiting examples of suitable natural flavors, some of which canreadily be simulated with synthetic agents or combinations thereof,include almond, anise, apple, apricot, bergamot, blackberry,blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove,coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig,ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt,mandarin, molasses, nutmeg, mixed berry, orange, peach, pear,peppermint, pineapple, raspberry, rose, spearmint, strawberry,tangerine, tea, vanilla, wintergreen, etc. Also useful, particularlywhere the formulation is intended primarily for pediatric use, istutti-frutti or bubblegum flavor, a compounded flavoring agent based onfruit flavors. Presently preferred flavoring agents include anise,cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry),grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be usedsingly or in combinations of two or more.

In further embodiments, the lisinopril oral liquid formulation describedherein comprises a coloring agent for identity and/or aestheticpurposes. Suitable coloring agents illustratively include FD&C Red No.3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2,D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixturesthereof.

In further embodiments, the lisinopril oral liquid formulation describedherein comprises a thickener. Thickeners impart viscosity or weight tothe resultant liquid forms from the lisinopril formulation describedherein. Exemplary thickeners include dextrin, cellulose derivatives(ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose,and the like) starches, pectin, polyethylene glycol, polyethylene oxide,trehalose and certain gums (xanthan gum, locust bean gum, etc.). Incertain embodiments, the lisinopril oral liquid formulations comprise athickener.

Additional excipients are contemplated in the lisinopril oral liquidformulation embodiments. These additional excipients are selected basedon function and compatibility with the lisinopril oral liquidformulations described herein and may be found, for example inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975);Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (NewYork, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999),herein incorporated by reference in their entirety.

Preparation of Lisinopril Oral Liquid Formulation

Preparation of the lisinopril oral liquid formulation described hereinincludes any known pharmaceutical method. In one embodiment, thelisinopril oral liquid formulation described herein is prepared bydissolving the buffer, the preservative, lisinopril, and the sweetenerin water and adjusting the pH as needed with sodium hydroxide orhydrochloric acid. In one embodiment, the oral lisinopril oral liquidformulation described herein is prepared by dissolving citric acidanhydrous, sodium citrate anhydrous, sodium benzoate, lisinoprildihydrate, and xylitol in water and adjusting the pH as needed withsodium hydroxide or hydrochloric acid. In some embodiments, the order ofaddition does not matter. In some embodiments, the lisinopril dissolvesslightly slower if added after the xylitol. In some embodiments, the pHdoes not need to be adjusted with sodium hydroxide or hydrochloric acid.

Provided herein is a process for preparing a stable oral liquidformulation comprising lisinopril, xylitol, a buffer, and sodiumbenzoate, the process which comprises the step of adding about 0.86mg/ml anhydrous citric acid, about 1.44 mg/ml anhydrous sodium citrateanhydrous, about 0.80 mg/ml sodium benzoate, about 1.09 mg/ml lisinoprildihydrate, and about 150 mg/ml xylitol to water; adjusting the volume tothe desired volume by adding more water; and adjusting the pH to 4.9 byadding sodium hydroxide or hydrochloric acid.

Stability

The main lisinopril degradants are lisinopril diketopiperazine (alsoknown as: Related Compound A) and lisinopril hydrolysate.

The lisinopril oral liquid formulations described herein are stable invarious storage conditions including refrigerated, ambient andaccelerated conditions. Stable as used herein refer to lisinopril oralliquid formulations having about 95% or greater of the initiallisinopril amount and about 5 w/w or less total impurities or relatedsubstances at the end of a given storage period. The percentage ofimpurities is calculated from the amount of impurities relative to theamount of lisinopril. Stability is assessed by HPLC or any other knowntesting method. In some embodiments, the stable lisinopril oral liquidformulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5%w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w totalimpurities or related substances. In other embodiments, the stablelisinopril oral liquid formulations have about 5 w/w total impurities orrelated substances. In yet other embodiments, the stable lisinopril oralliquid formulations have about 4% w/w total impurities or relatedsubstances. In yet other embodiments, the stable lisinopril oral liquidformulations have about 3% w/w total impurities or related substances.In yet other embodiments, the stable lisinopril oral liquid formulationshave about 2% w/w total impurities or related substances. In yet otherembodiments, the stable lisinopril oral liquid formulations have about1% w/w total impurities or related substances.

At refrigerated and ambient conditions, the lisinopril oral liquidformulations described herein are stable for at least 1 month, at least2 months, at least 3 months, at least 6 months, at least 9 months, atleast 12 months, at least 15 months, at least 18 months, at least 24months, at least 30 months and at least 36 months. At acceleratedconditions, the lisinopril oral liquid formulations described herein arestable for at least 1 month, at least 2 months, at least 3 months, atleast 4 months, at least 5 months, at least 6 months, at least 7 months,at least 8 months, at least 9 months, at least 10 months, at least 11months or at least 12 months. Accelerated conditions include temperatureand/or relative humidity (RH) that are above ambient levels (e.g. 25±5°C.; 55±10% RH). In some instances, an accelerated condition is at about30° C., about 35° C., about 40° C., about 45° C., about 50° C., about55° C. or about 60° C. In other instances, an accelerated condition isabove 65% RH, about 70% RH, about 75% RH or about 80% RH. In furtherinstances, an accelerated condition is about 40° C. or 60° C. at ambienthumidity. In yet further instances, an accelerated condition is about40° C. at 75±5% RH humidity.

Provided herein are various embodiments of lisinopril oral liquidformulations. In one aspect, the lisinopril oral liquid formulationcomprises (i) lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) a sweetener that is xylitol, (iii) a buffercomprising citric acid (iv) a preservative that is sodium benzoate, and(v) water; wherein the pH of the formulation is between about 4 andabout 5; and wherein the formulation is stable at about 25±5° C. for atleast 12 months. In some embodiments, the buffer further comprisessodium citrate.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol,(iii) a buffer comprising about 0.86 mg/ml citric acid, (iv) about 0.8mg/ml of a preservative that is sodium benzoate; and (v) water; whereinthe pH of the formulation is between about 4 and about 5; and whereinthe formulation is stable at about 25±5° C. for at least 12 months. Insome embodiments, the buffer further comprises about 1.44 mg/ml sodiumcitrate.

In one aspect, the lisinopril oral liquid formulation comprises (i)lisinopril or a pharmaceutically acceptable salt or solvate thereof,(ii) a sweetener that is sucralose, (iii) a buffer comprising citricacid, (iv) a preservative that is sodium benzoate; and (v) water whereinthe formulation is stable at about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 2 mg/ml of a sweetener that is sucralose,(iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 0.8mg/ml of a preservative that is sodium benzoate; and (v) water whereinthe formulation is stable at about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 0.7 mg/ml of a sweetener that is sucralose,(iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 0.8mg/ml of a preservative that is sodium benzoate; and (v) water whereinthe formulation is stable at about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)lisinopril or a pharmaceutically acceptable salt or solvate thereof,(ii) of a sweetener that is sucralose, (iii) a buffer comprising citricacid, (iv) a preservative that is methyl paraben, (v) a preservativethat is propylparaben, and (vi) water; wherein the formulation is stableat about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 2 mg/ml of a sweetener that is sucralose,(iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 1.72mg/ml of a preservative that is methyl paraben sodium, (v) about 0.17mg/mL of a preservative that is propylparaben sodium, and (vi) water;wherein the formulation is stable at about 25±5° C. for at least 12months.

In one aspect, the lisinopril oral liquid formulation comprises (i)lisinopril or a pharmaceutically acceptable salt or solvate thereof,(ii) a sweetener that is xylitol, (iii) a buffer comprising citric acid,(iv) a preservative that is sodium benzoate; and (v) water; wherein theformulation is stable at about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol,(iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 0.8mg/ml of a preservative that is sodium benzoate; and (v) water; whereinthe formulation is stable at about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation, comprises (i)lisinopril or a pharmaceutically acceptable salt or solvate thereof,(ii) a sweetener that is xylitol, (iii) a buffer comprising citric acid,(iv) a preservative that is methyl paraben, (v) a preservative that ispropylparaben; and (vi) water; wherein the formulation is stable atabout 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 150 mg/ml of a sweetener that is xylitol,(iii) a buffer comprising about 1.92 mg/ml citric acid, (iv) about 1.72mg/ml of a preservative that is methyl paraben sodium, (v) about 0.17mg/mL of a preservative that is propylparaben sodium; and (vi) water;wherein the formulation is stable at about 25±5° C. for at least 12months.

In one aspect, the lisinopril oral liquid formulation comprises (i)lisinopril or a pharmaceutically acceptable salt or solvate thereof,(ii) a sweetener that is xylitol, (iii) a second sweetener that issucralose (iv) a buffer comprising citric acid, (v) a preservative thatis methyl paraben, (vi) a preservative that is propylparaben; and (vii)water; wherein the formulation is stable at about 25±5° C. for at least12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 100 mg/ml of a sweetener that is xylitol,(iii) about 2 mg/ml of a second sweetener that is sucralose (iv) abuffer comprising about 1.92 mg/ml citric acid, (v) about 1.72 mg/ml ofa preservative that is methyl paraben sodium, (vi) about 0.17 mg/mL of apreservative that is propylparaben sodium; and (vii) water; wherein theformulation is stable at about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)lisinopril or a pharmaceutically acceptable salt or solvate thereof,(ii) a sweetener that is sucralose, (iii) a buffer comprising sodiumphosphate, (iv) a preservative that is methyl paraben, (v) apreservative that is propylparaben, and (vi) water; wherein theformulation is stable at about 25±5° C. for at least 12 months.

In one aspect, the lisinopril oral liquid formulation comprises (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof, (ii) about 0.7 mg/ml of a sweetener that is sucralose,(iii) a buffer comprising about 2.4 mg/ml monobasic sodium phosphate,(iv) about 1.72 mg/ml of a preservative that is methyl paraben sodium,(v) about 0.225 mg/mL of a preservative that is propylparaben sodium,and (vi) water; wherein the formulation is stable at about 25±5° C. forat least 12 months.

Lisinopril Powder Formulations

In another aspect, lisinopril oral liquid formulations described hereinare prepared from the reconstitution of a lisinopril powder formulation.In some embodiments, the lisinopril powder formulation comprisinglisinopril, a sweetener, a preservative, and optionally an excipient isdissolved in water, a buffer, other aqueous solvent, or a liquid to forma lisinopril oral liquid formulation. In one embodiment, the sweeteningagent is xylitol. In one embodiment, the sweetener is mannitol. In oneembodiment, the sweetening agent is sucralose. In another embodiment,the preservative is sodium benzoate. In one embodiment, the preservativeis a paraben preservative. In one aspect, the lisinopril powderformulation described herein comprises lisinopril, xylitol, and sodiumbenzoate. In some embodiments, the lisinopril powder formulation hereinfurther comprises a flavoring agent. In some embodiments, the lisinoprilpowder formulation herein further comprises one or more bufferingagents.

In some embodiments, lisinopril is present in about 0.5% w/w to about 5%w/w of the powder formulation. In other embodiments, Lisinopril ispresent in about 0.5 w/w, about 0.55 w/w, about 0.6% w/w, about 0.65w/w, about 0.7% w/w, about 0.75 w/w, about 0.8% w/w, about 0.85 w/w,about 0.9% w/w, about 0.95 w/w, about 1 w/w, about 1.1% w/w, about 1.2%w/w, about 1.3% w/w, about 1.4% w/w, about 1.5 w/w, about 1.6% w/w,about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2% w/w, about 2.1%w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w, about 2.5 w/w,about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about 2.9% w/w, about 3%w/w, about 3.1% w/w, about 3.2% w/w, about 3.3% w/w, about 3.4% w/w,about 3.5% w/w, about 3.6% w/w, about 3.7% w/w, about 3.8% w/w, about3.9% w/w, about 4% w/w, about 4.1% w/w, about 4.2% w/w, about 4.3% w/w,about 4.4% w/w, about 4.5 w/w, about 4.6% w/w, about 4.7% w/w, about4.8% w/w, about 4.9% w/w, or about 5% w/w of the powder formulation. Insome embodiments, lisinopril is present in about 0.5 w/w to about 1 w/wof the powder formulation. In some embodiments, lisinopril is present inabout 0.6% w/w to about 0.8% w/w of the powder formulation. In someembodiments, lisinopril is present in about 0.7% w/w of the powderformulation.

In some embodiments, lisinopril is present in about 10% w/w to about 20%w/w of the powder formulation. In other embodiments, lisinopril ispresent in about 10% w/w, about 10.5 w/w, about 11% w/w, about 11.5 w/w,about 12% w/w, about 12.5 w/w, about 13% w/w, about 13.5 w/w, about 14%w/w, about 14.5 w/w, about 15 w/w, about 15.5 w/w, about 16% w/w, about16.5% w/w, about 17% w/w, about 17.5 w/w, about 18% w/w, about 18.5 w/w,about 19% w/w, about 19.5 w/w, or about 20% w/w of the powderformulation. In some embodiments, lisinopril is present in about 14% w/wto about 16% w/w of the powder formulation. In some embodiments,lisinopril is present in about 17% w/w to about 19% w/w of the powderformulation.

Various amounts and concentrations of other components (sweeteners,buffers, preservatives, and the like) in the lisinopril powderformulations are found in the previous section describing the amountsand concentrations for the analogous lisinopril oral liquidformulations. For example, in some embodiments where sucralose ispresent in about 20% w/w to about 40% w/w of the solids in the oralliquid formulation; in an analogous lisinopril powder formulation,sucralose would be about 20% w/w to about 40% w/w in the powderformulation. In some embodiments where sodium benzoate is present inabout 10% w/w to about 15% w/w of the solids in the oral liquidformulation, in an analogous lisinopril powder formulation sodiumbenzoate is present in about 10% w/w to about 15 w/w in the powderformulation.

Liquid vehicles suitable for the lisinopril powder formulations to bereconstituted into an oral solution described herein are selected for aparticular oral liquid formulation (solution, suspension, etc.) as wellas other qualities such as clarity, toxicity, viscosity, compatibilitywith excipients, chemical inertness, palatability, odor, color andeconomy. Exemplary liquid vehicles include water, ethyl alcohol,glycerin, propylene glycol, syrup (sugar or other sweetener based, e.g.,Ora-Sweet® SF sugar-free flavored syrup), juices (apple, grape, orange,cranberry, cherry, tomato and the like), other beverages (tea, coffee,soft drinks, milk and the like), oils (olive, soybean, corn, mineral,castor and the like), and combinations or mixtures thereof. Certainliquid vehicles, e.g., oil and water, can be combined together to formemulsions. In some embodiments, water is used for as a vehicle for alisinopril oral liquid formulation. In other embodiments, a syrup isused for as a vehicle for a lisinopril oral liquid formulation. In yetother embodiments, a juice is used for as a vehicle for a lisinopriloral liquid formulation.

Buffering agents maintain the pH of the liquid lisinopril formulation.Non-limiting examples of buffering agents include, but are not limitedto sodium bicarbonate, potassium bicarbonate, magnesium hydroxide,magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminumhydroxide/sodium bicarbonate co precipitate, mixture of an amino acidand a buffer, a mixture of aluminum glycinate and a buffer, a mixture ofan acid salt of an amino acid and a buffer, and a mixture of an alkalisalt of an amino acid and a buffer. Additional buffering agents includecitric acid, sodium citrate, sodium tartarate, sodium acetate, sodiumcarbonate, sodium polyphosphate, potassium polyphosphate, sodiumpyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate,dipotassium hydrogenphosphate, trisodium phosphate, tripotassiumphosphate, sodium acetate, potassium metaphosphate, magnesium oxide,magnesium hydroxide, magnesium carbonate, magnesium silicate, calciumacetate, calcium glycerophosphate, calcium chloride, calcium hydroxide,calcium lactate, calcium carbonate, calcium bicarbonate, and othercalcium salts. Some buffering agents also impart effervescent qualitieswhen a powder is reconstituted in a solution.

In some embodiments, the reconstituted oral liquid formulation comprisesa buffer. In some embodiments, the buffer comprises citric acid andsodium citrate.

In further embodiments, the lisinopril powder formulation describedherein comprises additional excipients including, but not limited to,glidants, flavoring agents, coloring agents and thickeners. Additionalexcipients such as bulking agents, tonicity agents and chelating agentsare within the scope of the embodiments.

Glidants are substances that improve flowability of a powder. Suitableglidants include, but are not limited to, calcium phosphate tribasic,calcium silicate, cellulose (powdered), colloidal silicon dioxide,magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talcand the like. In some embodiments, the lisinopril powder formulationsdescribed herein comprise a glidant.

In another embodiment, the lisinopril powder formulation describedherein comprises a flavoring agent or flavorant to enhance the taste oraroma of the formulation in liquid form. Suitable natural or syntheticflavoring agents can be selected from standard reference books, forexample Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).Non-limiting examples of suitable natural flavors, some of which canreadily be simulated with synthetic agents or combinations thereof,include almond, anise, apple, apricot, bergamot, blackberry,blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove,coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig,ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt,mandarin, molasses, nutmeg, mixed berry, orange, peach, pear,peppermint, pineapple, raspberry, rose, spearmint, strawberry,tangerine, tea, vanilla, wintergreen, etc. Also useful, particularlywhere the formulation is intended primarily for pediatric use, istutti-frutti or bubblegum flavor, a compounded flavoring agent based onfruit flavors. Presently preferred flavoring agents include anise,cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry),grape, bubblegum, vanilla, and mixed berry. Flavoring agents can be usedsingly or in combinations of two or more.

In further embodiments, the lisinopril powder formulation describedherein comprises a coloring agent for identity and/or aestheticpurposes. Suitable coloring agents illustratively include FD&C Red No.3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2,D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixturesthereof.

In further embodiments, the lisinopril powder formulation describedherein comprises a thickener. Thickeners impart viscosity or weight tothe resultant liquid forms from the lisinopril formulation describedherein. Exemplary thickeners include dextrin, cellulose derivatives(ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose,and the like) starches, pectin, polyethylene glycol, polyethylene oxide,trehalose and certain gums (xanthan gum, locust bean gum, etc.).

Additional excipients are contemplated in the lisinopril powderformulation embodiments. These additional excipients are selected basedon function and compatibility with the the lisinopril powder formulationdescribed herein and may be found, for example in Remington: The Scienceand Practice of Pharmacy, Nineteeth Ed (Easton, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,(Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L.,Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980);and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed(Lippincott Williams & Wilkins 1999), herein incorporated by referencein their entirety.

In some embodiments, the lisinopril oral liquid formulation preparedfrom the powder formulations described herein are homogenous. Homogenousliquids as used herein refer to those liquids that are uniform inappearance, identity, consistency and drug concentration per volume.Non-homogenous liquids include such liquids that have varied coloring,viscosity and/or aggregation of solid particulates, as well asnon-uniform drug concentration in a given unit volume. Homogeneity inliquids are assessed by qualitative identification or appearance testsand/or quantitative HPLC testing or the like. The mixing methods andexcipients described herein are selected to impart a homogenous qualityto a resultant lisinopril oral liquid formulation.

Mixing methods encompass any type of mixing that result in a homogenouslisinopril oral liquid formulation. In some embodiments, a quantity of alisinopril powder formulation is added to a liquid vehicle and thenmixed by a stirring, shaking, swirling, agitation element or acombination thereof. In certain instances, a fraction of a lisinoprilpowder formulation (i.e., one-half, one-third, one-fourth, etc.) isadded to a liquid vehicle, mixed by stirring, shaking, swirling,agitation or a combination thereof, and the subsequent powderfraction(s) is added and mixed. In other embodiments, a liquid vehicleis added to a lisinopril powder formulation in a container, for example,a bottle, vial, bag, beaker, syringe, or the like. The container is thenmixed by stirring, shaking, swirling, agitation, inversion or acombination thereof. In certain instances, a fractional volume of theliquid vehicle (i.e., one-half, one-third, one-fourth volume, etc.) isadded to a lisinopril powder formulation in a container, mixed bystirring, shaking, swirling, agitation, inversion or a combinationthereof; and the subsequent liquid fraction(s) is added and mixed. Incertain instances, a one-half fractional volume of the liquid vehicle isadded to a lisinopril powder formulation in a container and mixing byshaking; the other one-half fractional volume of the liquid vehicle isthen subsequently added and mixed. In any of the above embodiments,mixing (i.e., stirring, shaking, swirling, agitation, inversion or acombination thereof) occurs for a certain time intervals such as about10 seconds, about 20 seconds, about 30 seconds, about 45 seconds, about60 seconds, about 90 seconds, about 120 seconds, about 2.5 minutes,about 3 minutes, about 3.5 minutes, about 4 minutes, or about 5 minutes.In embodiments, where there are two or more mixing steps, the timeintervals for each mixing can be the same (e.g., 2×10 seconds) ordifferent (e.g., 10 seconds for first mixing and 20 seconds for secondmixing). In any of the above embodiments, a lisinopril oral liquidformulation is allowed to stand for a period of time such as about 10minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1hour, about 1.5 hours or about 2 hours, to allow any air bubblesresultant from any of the mixing methods to dissipate.

Stability of Lisinopril Powder Formulations

The lisinopril powder formulations described herein are stable invarious storage conditions including refrigerated, ambient andaccelerated conditions. Stable as used herein refer to lisinopril powderformulations having about 95% or greater of the initial lisinoprilamount and 5 w/w or less total impurities or related substances at theend of a given storage period. The percentage of impurities iscalculated from the amount of impurities relative to the amount oflisinopril. Stability is assessed by HPLC or any other known testingmethod. In some embodiments, the stable lisinopril powder formulationshave about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2%w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities orrelated substances. In other embodiments, the stable lisinopril powderformulations have about 5 w/w total impurities or related substances. Inyet other embodiments, the stable lisinopril powder formulations haveabout 4% w/w total impurities or related substances. In yet otherembodiments, the stable lisinopril powder formulations have about 3% w/wtotal impurities or related substances. In yet other embodiments, thestable lisinopril powder formulations have about 2% w/w total impuritiesor related substances. In yet other embodiments, the stable lisinoprilpowder formulations have about 1 w/w total impurities or relatedsubstances.

At refrigerated and ambient conditions, in some embodiments, thelisinopril powder formulations described herein are stable for at least1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16weeks, 20 weeks, at least 24 weeks, at least 30 weeks, or at least 36weeks. At accelerated conditions, in some embodiments, the lisinoprilpowder formulations described herein are stable for at least 1 week, atleast 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, atleast 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, atleast 10 weeks, at least 11 weeks or at least 12 weeks. Acceleratedconditions include temperature and/or relative humidity (RH) that areabove ambient levels (e.g. 25±4° C.; 55±10% RH). In some instances, anaccelerated condition is at about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 55° C. or about 60° C. In otherinstances, an accelerated condition is above 65% RH, about 70% RH, about75% RH or about 80% RH. In further instances, an accelerated conditionis about 40° C. or 60° C. at ambient humidity. In yet further instances,an accelerated condition is about 40° C. at 75±5% RH humidity.

Kits and Articles of Manufacture

For the lisinopril powder and liquid formulations described herein, kitsand articles of manufacture are also described. Such kits can comprise acarrier, package, or container that is compartmentalized to receive oneor more containers such as vials, tubes, and the like, each of thecontainer(s) comprising one of the separate elements to be used in amethod described herein including a lisinopril powder or liquidformulation. Suitable containers include, for example, bottles, vials,syringes, and test tubes. The containers can be formed from a variety ofmaterials such as glass or plastic.

A kit will typically may comprise one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for a lisinopril powder or liquid formulation describedherein. Non-limiting examples of such materials include, but not limitedto, buffers, diluents, filters, needles, syringes, syringe adapter,carrier, package, container, vial and/or tube labels listing contentsand/or instructions for use, and package inserts with instructions foruse associated with a lisinopril powder or liquid formulation. A set ofinstructions will also typically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

Methods

Provided herein, in one aspect, are methods of treatment comprisingadministration of the lisinopril oral liquid formulations describedherein to a subject. In some embodiments, the lisinopril oral liquidformulations described herein treat hypertension in a subject.Hypertension as used herein includes both primary (essential)hypertension or secondary hypertension. In certain instances,hypertension is classified in cases when blood pressure values aregreater than or equal to 140/90 (systolic/diastolic) mm Hg in a subject.In certain instances, the lisinopril oral liquid formulations describedherein treat a subject having a blood pressure value greater than orequal to 140/90 mm Hg. In certain instances, the lisinopril oral liquidformulations described herein treat primary (essential) hypertension ina subject. In other instances, the lisinopril oral liquid formulationsdescribed herein treat secondary hypertension in a subject.

In other embodiments, the lisinopril oral liquid formulations describedherein treat prehypertension in a subject. Prehypertension as usedherein refers to cases where a subject's blood pressure is elevatedabove normal but not to the level considered to be hypertension. In someinstances, prehypertension is classified in cases when blood pressurevalues are 120-139/80-89 mm Hg. In certain instances, the lisinopriloral liquid formulations described herein treat a subject having a bloodpressure value of 120-139/80-89 mm Hg.

In yet other embodiments, the lisinopril oral liquid formulationsdescribed herein are prophylactically administered to subjects suspectedof having, predisposed to, or at risk of developing hypertension. Insome embodiments, the administration of lisinopril oral liquidformulations described herein allow for early intervention prior toonset of hypertension. In certain embodiments, upon detection of abiomarker, environmental, genetic factor, or other marker, thelisinopril oral liquid formulations described herein areprophylactically administered to subjects.

In further embodiments, the lisinopril oral liquid formulationsdescribed herein treat heart failure (e.g., symptomatic congestive),asymptomatic left ventricular dysfunction, myocardial infarction,diabetic nephropathy and chronic renal failure. In certain instances,the lisinopril oral liquid formulations described herein is indicated asadjunctive therapy in the management of heart failure in patients whoare not responding adequately to diuretics and digitalis. In certaininstances, the lisinopril oral liquid formulations described hereintreat symptomatic congestive heart failure. In other instances, thelisinopril oral liquid formulations described herein treat asymptomaticleft ventricular dysfunction. In further instances, the lisinopril oralliquid formulations described herein treat myocardial infarction. Infurther instances, the lisinopril oral liquid formulations describedherein treat hemodynamically stable patients within 24 h of acutemyocardial infarction. In yet further instances, the lisinopril oralliquid formulations described herein treat diabetic nephropathy. In yetfurther instances, the lisinopril oral liquid formulations describedherein treat chronic renal failure. In yet further instances, thelisinopril oral liquid formulations described herein is used inpreventing renal and retinal complications of diabetes.

Dosing

In one aspect, the lisinopril oral liquid formulations are used for thetreatment of diseases and conditions described herein. In addition, amethod for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration oflisinopril oral liquid formulations in therapeutically effective amountsto said subject.

Dosages of lisinopril oral liquid formulations described can bedetermined by any suitable method. Maximum tolerated doses (MTD) andmaximum response doses (MRD) for lisinopril can be determined viaestablished animal and human experimental protocols as well as in theexamples described herein. For example, toxicity and therapeuticefficacy of lisinopril can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, including, but notlimited to, for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between the toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratiobetween LD₅₀ and ED₅₀. Lisinopril dosages exhibiting high therapeuticindices are of interest. The data obtained from cell culture assays andanimal studies can be used in formulating a range of dosage for use inhuman. The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with minimal toxicity.The dosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. Additional relativedosages, represented as a percent of maximal response or of maximumtolerated dose, are readily obtained via the protocols.

In some embodiments, the amount of a given lisinopril oral liquidformulation that corresponds to such an amount varies depending uponfactors such as the particular lisinopril salt or solvate, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the liquidformulation type, the condition being treated, and the subject or hostbeing treated.

In some embodiments, the lisinopril oral liquid formulations describedherein are provided in a dose per day from about 0.01 mg to 100 mg, fromabout 0.1 mg to about 80 mg, from about 1 to about 60, from about 2 mgto about 40 mg of lisinopril. In certain embodiments, the lisinopriloral liquid formulations described herein are provided in a daily doseof about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.4mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 1.5 mg, about 2 mg,about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 76, mg, about 80 mg, about 85 mg, about 90 mg or about 100mg, or any range derivable therein. In certain instances, the lisinopriloral liquid formulations described herein are provided in a dose per dayof about 1 mg. In certain instances, the lisinopril oral liquidformulations described herein are provided in a dose per day of about 2mg. In certain instances, the lisinopril oral liquid formulationsdescribed herein are provided in a dose per day of about 3 mg. Incertain instances, the lisinopril oral liquid formulations describedherein are provided in a dose per day of about 4 mg. In certaininstances, the lisinopril oral liquid formulations described herein areprovided in a dose per day of about 5 mg. In certain instances, thelisinopril oral liquid formulations described herein are provided in adose per day of about 6 mg. In certain instances, the lisinopril oralliquid formulations described herein are provided in a dose per day ofabout 7 mg. In certain instances, the lisinopril oral liquidformulations described herein are provided in a dose per day of about 8mg. In certain instances, the lisinopril oral liquid formulationsdescribed herein are provided in a dose per day of about 9 mg. Incertain instances, the lisinopril oral liquid formulations describedherein are provided in a dose per day of about 10 mg. In certaininstances, the lisinopril oral liquid formulations described herein areprovided in a dose per day of about 11 mg. In certain instances, thelisinopril oral liquid formulations described herein are provided in adose per day of about 12 mg. The dose per day described herein can begiven once per day or multiple times per day in the form of sub-dosesgiven b.i.d., t.i.d., q.i.d., or the like where the number of sub-dosesequal the dose per day.

In further embodiments, the daily dosages appropriate for the lisinopriloral liquid formulations described herein are from about 0.01 to about1.0 mg/kg per body weight. In one embodiment, the daily dosagesappropriate for the lisinopril oral liquid formulations are from about0.02 to about 0.8 mg/kg lisinopril per body weight. In anotherembodiment, the daily dosage appropriate for the lisinopril oral liquidformulations are from about 0.05 to about 0.6 mg/kg per body weight. Inanother embodiment, the daily dosage appropriate for the lisinopril oralliquid formulations is about 0.05 mg/kg, about 0.06 mg/kg, about 0.07mg/kg, about 0.08 mg/kg, about 0.10 mg/kg, about 0.15 mg/kg, about 0.20mg/kg, about 0.25 mg/kg, about 0.30 mg/kg, about 0.40 mg/kg, about 0.50mg/kg, about 0.60 mg/kg, about 0.61 mg/kg, about 0.62 mg/kg, about 0.63mg/kg, about 0.64 mg/kg, or about 0.65 mg/kg.

In other embodiments the lisinopril oral liquid formulations areprovided at the maximum tolerated dose (MTD) for lisinopril. In otherembodiments, the amount of the lisinopril oral liquid formulationsadministered is from about 10% to about 90% of the maximum tolerateddose (MTD), from about 25% to about 75% of the MTD, or about 50% of theMTD. In particular embodiments, the amount of the lisinopril oral liquidformulations administered is from about 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, orhigher, or any range derivable therein, of the MTD for lisinopril.

In further embodiments, the lisinopril oral liquid formulations areprovided in a dosage that is similar, comparable or equivalent to adosage of a known lisinopril tablet formulation. In other embodiments,the lisinopril oral liquid formulations are provided in a dosage thatprovides similar, comparable or equivalent pharmacokinetic parameters(e.g., AUC, C_(max), T_(max), C_(min), T_(1/2)) as a dosage of a knownlisinopril tablet formulation. Similar, comparable or equivalentpharmacokinetic parameters, in some instances, refer to within 80% to125%, 80% to 120%, 85% to 125%, 90% to 110%, or increments therein, ofthe given values. It should be recognized that the ranges can, but neednot be symmetrical, e.g., 85% to 105%.

Administration

Administration of a lisinopril oral liquid formulation is at a dosagedescribed herein or at other dose levels and formulations determined andcontemplated by a medical practitioner. In certain embodiments, thelisinopril oral liquid formulations described herein are administeredfor prophylactic and/or therapeutic treatments. In certain therapeuticapplications, the lisinopril oral liquid formulations are administeredto a patient already suffering from a disease, e.g., hypertension, in anamount sufficient to cure the disease or at least partially arrest orameliorate the symptoms, e.g., lower blood pressure. Amounts effectivefor this use depend on the severity of the disease, previous therapy,the patient's health status, weight, and response to the lisinoprilformulations, and the judgment of the treating physician.Therapeutically effective amounts are optionally determined by methodsincluding, but not limited to, a dose escalation clinical trial.

In prophylactic applications, the lisinopril oral liquid formulationsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, e.g., hypertension. Such anamount is defined to be a “prophylactically effective amount or dose.”In this use, the precise amounts also depend on the patient's state ofhealth, weight, and the like. When used in a patient, effective amountsfor this use will depend on the risk or susceptibility of developing theparticular disease, previous therapy, the patient's health status andresponse to the lisinopril formulations, and the judgment of thetreating physician.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of a lisinopril oralliquid formulation described herein are administered chronically, thatis, for an extended period of time, including throughout the duration ofthe patient's life in order to ameliorate or otherwise control or limitthe symptoms of the patient's disease. In other embodiments,administration of a lisinopril oral liquid formulation continues untilcomplete or partial response of a disease.

In certain embodiments wherein a patient's status does improve, the doseof a lisinopril oral liquid formulation being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). In specific embodiments, the length ofthe drug holiday is between 2 days and 1 year, including by way ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,320 days, 350 days, and 365 days. The dose reduction during a drugholiday is, by way of example only, by 10%-100%, including by way ofexample only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, and 100%.

In some embodiments, lisinopril oral liquid formulations describedherein are administered chronically. For example, in some embodiments, alisinopril oral liquid formulation is administered as a continuous dose,i.e., administered daily to a subject. In some other embodiments,lisinopril oral liquid formulations described herein are administeredintermittently (e.g. drug holiday that includes a period of time inwhich the formulation is not administered or is administered in areduced amount).

In some embodiments a lisinopril oral liquid formulation is administeredto a subject who is in a fasted state. A fasted state refers to asubject who has gone without food or fasted for a certain period oftime. General fasting periods include at least 4 hours, at least 6hours, at least 8 hours, at least 10 hours, at least 12 hours, at least14 hours and at least 16 hours without food. In some embodiments, alisinopril oral liquid formulation is administered orally to a subjectwho is in a fasted state for at least 8 hours. In other embodiments, alisinopril oral liquid formulation is administered to a subject who isin a fasted state for at least 10 hours. In yet other embodiments, alisinopril oral liquid formulation is administered to a subject who isin a fasted state for at least 12 hours. In other embodiments, alisinopril oral liquid formulation is administered to a subject who hasfasted overnight.

In other embodiments a lisinopril oral liquid formulation isadministered to a subject who is in a fed state. A fed state refers to asubject who has taken food or has had a meal. In certain embodiments, alisinopril oral liquid formulation is administered to a subject in a fedstate 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal,20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certaininstances, a lisinopril oral liquid formulation is administered to asubject in a fed state 30 minutes post-meal. In other instances, alisinopril oral liquid formulation is administered to a subject in a fedstate 1 hour post-meal. In yet further embodiments, a lisinopril oralliquid formulation is administered to a subject with food.

In further embodiments described herein, a lisinopril oral liquidformulation is administered at a certain time of day for the entireadministration period. For example, a lisinopril oral liquid formulationcan be administered at a certain time in the morning, in the evening, orprior to bed. In certain instances, a lisinopril oral liquid formulationis administered in the morning. In other embodiments, a lisinopril oralliquid formulation can be administered at different times of the day forthe entire administration period. For example, a lisinopril oral liquidformulation can be administered on 8:00 am in the morning for the firstday, 12 pm noon for the next day or administration, 4 pm in theafternoon for the third day or administration, and so on.

Further Combinations

The treatment of certain diseases or conditions (e.g., hypertension,heart failure, myocardial infarction and the like) in a subject with alisinopril oral liquid formulation described herein encompass additionaltherapies and treatment regimens with other agents in some embodiments.Such additional therapies and treatment regimens can include anothertherapy, e.g., additional anti-hypertensives, for treatment of theparticular disease or condition in some embodiments. Alternatively, inother embodiments, additional therapies and treatment regimens includeother agents used to treat adjunct conditions associated with thedisease or condition or a side effect from the lisinopril oral liquidformulation in the therapy.

Additional agents for use in combination with a lisinopril oral liquidformulation described herein include, but are not limited to, diuretics(loop, thiazide, potassium-sparing, and the like), beta blockers(metoprolol, propanolol, pronethalol, and the like), alpha blockers(phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like),mixed alpha and beta blockers (bucindolol, carvedilol, labetalol),calcium channel blockers (dihydropyridines such as nifedipine,amlodipine, etc., dilitazem, verapamil and the like), angiotensin IIreceptor antagonists (saralasin, losartan, eprosartin, irbesartan,valsartan, and the like), other ACE inhibitors (captopril, quinapril,ramipril, enalapril, zofenopril, and the like), aldosterone antagonists(eplerenone, spironolactone and the like), vasodilators (hydralazine andthe like) and alpha-2 agonists (clonidine, moxonidine, guanabenz and thelike).

Certain Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes the standardlevel of error for the device or method being employed to determine thevalue. The use of the term “or” in the claims is used to mean “and/or”unless explicitly indicated to refer to alternatives only or thealternatives are mutually exclusive, although the disclosure supports adefinition that refers to only alternatives and to “and/or.” The terms“comprise,” “have” and “include” are open-ended linking verbs. Any formsor tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the description includes instances where the events occurs andinstances where it does not.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In some embodiments, a therapeutic agent such aslisinopril is directed to the treatment and/or the amelioration of,reversal of, or stabilization of the symptoms of hypertension describedherein.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. Thus, as used herein, the term “administering”, when used inconjunction with a lisinopril formulation, can include, but is notlimited to, providing a lisinopril formulation into or onto the targettissue; providing a lisinopril formulation systemically to a patient by,e.g., oral administration whereby the therapeutic reaches the targettissue or cells. “Administering” a formulation may be accomplished byinjection, topical administration, and oral administration or by othermethods alone or in combination with other known techniques.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals. Asused herein, the terms “patient,” “subject” and “individual” areintended to include living organisms in which certain conditions asdescribed herein can occur. Examples include humans, monkeys, cows,sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. Ina preferred embodiment, the patient is a primate. In certainembodiments, the primate or subject is a human. In certain instances,the human is an adult. In certain instances, the human is child. Infurther instances, the human is 12 years of age or younger. In certaininstances, the human is elderly. In other instances, the human is 60years of age or older. Other examples of subjects include experimentalanimals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.The experimental animal can be an animal model for a disorder, e.g., atransgenic mouse with hypertensive pathology. A patient can be a humansuffering from hypertension, or its variants or etiological forms.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “pharmaceutical formulation” shall mean a formulationcomprising at least one active ingredient, whereby the formulation isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology). As such,a non-limiting example of a “therapeutically effective amount” or“effective amount” of a formulation of the present disclosure may beused to inhibit, block, or reverse the activation, migration, orproliferation of cells or to effectively treat hypertension orameliorate the symptoms of hypertension.

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

EXAMPLES

The following examples are intended to illustrate but not limit thedisclosed embodiments.

Example A: Effect of pH on the Formation of Degradants in LisinoprilFormulations at 60° C.

Formulations were prepared containing lisinopril according to Table A-1.The components were dissolved in ˜15 mL water then additional water wasadded to bring each solution to 20 mL. The pH was adjusted to the finalvalue with ˜1N HCl or −0.5N NaOH. Five milliliters of each formulationwere transferred to each of four 3-dram glass screw-capped vials withTeflon inserts in the caps. The vials were placed into a 60° C. heatingchamber then removed and analyzed by HPLC at times of zero, ˜48 and −145hours.

TABLE A-1 Formulation (in mg) of Lisinopril Formulations at Varying pHand 50 mM Citrate Buffer Formulation Component A1 A2 A3 A4 A5 Lisinoprildihydrate^(a) 21.78 21.78 21.78 21.78 21.78 Mannitol 1000 1000 1000 1000Xylitol 1000 Citric acid, anhydrous 153.6 107.6 107.6 107.6 61.4 Sodiumcitrate, dihydrate 45.6 100 100 100 155 Sodium benzoate 20.0 20.0 20.020.0 20.0 Methylparaben sodium 34.4 Sucralose 15.0 15.0 15.0 15.0 15.0Sodium chloride 50.0 50.0 50.0 50.0 50.0 Grape flavor (powdered) 10.010.0 10.0 10.0 10.0 Water qs qs qs qs qs 20 mL 20 mL 20 mL 20 mL 20 mLpH 3.21 4.05 4.05 4.27 4.81 ^(a)= equivalent to 1 mg/mL lisinopril qs =sufficient quantity

The results of the HPLC analysis for the two main degradants in thesamples, lisinopril diketopiperazine and lisinopril hydrolysate, areprovided in Table A-2.

TABLE A-2 Primary Degradants Present in the Formulations (% w/w oflisinopril) Formulation Hours at 60° C. A1 A2 A3 A4 A5 LisinoprilDiketopiperazine 0 0.05 0.04 0.05 0.04 0.04 45.5 2.51 0.78 0.74 0.460.20 145.5 7.93 2.36 2.16 1.39 0.48 Lisinopril Hydrolysate 0 0.11 0.110.11 0.11 0.11 45.5 0.35 0.25 0.22 0.23 0.22 145.5 0.85 0.54 0.46 0.500.48

Example B: Stability of Powder and Solution Formulations of Lisinopril

Powder formulations were prepared according to Table B-1. All componentsin each formulation except mannitol or xylitol were added to a 2.5 Lpolypropylene screw capped bottle. The bottle was mixed by inversion ina Turbula mixer for 5 minutes. One-half of the mannitol or xylitol wasthen added, the components mixed for 5 minutes, then the other half ofthe mannitol or xylitol was added and a final mix of 5 minutes wascompleted. Five gram aliquots of each formulation were placed intoopaque high density polyethylene bottles. The bottles were screw-cappedand placed into storage at room temperature (19-23° C.) and at 40° C.±2°C.

One liter of solution formulation was prepared for each formulation byadding 66.67 grams of each powdered formulation to a 1 liter volumetricflask and adding about 500 mL water. The powder was dissolved withmixing then the contents of the flask were brought to 1 L withadditional water. Fifty milliliter aliquots of each formulation wereplaced into HDPE bottles. The bottles were screw-capped and placed intostorage at 5° C.±3° C., at room temperature (19-23° C.) and at 40° C.±2°C.

At various times, bottles were removed from the storage condition andanalyzed. The powder bottles were constituted with purified water toyield a final volume in each bottle of 75 mL.

TABLE B-1 Formulation of Lisinopril Formulations Component B1 B2 B3 B4B5 Powder Formulation (grams) Lisinopril dihydrate^(a) 10.4 10.4 10.410.4 3.05 Mannitol 481.7 485.0 487.7 484.4 Xylitol 141.2 Citric acid,anhydrous 43.3 52.8 38.38 29.0 12.7 Sodium citrate, 65.4 52.4 71.9 84.419.2 anhydrous Potassium sorbate 9.57 9.57 Sodium benzoate 9.57 9.572.81 Methylparaben sodium 11.0 11.01 3.35 3.35 3.23 Sucralose 7.18 7.187.18 7.18 2.10 Grape flavor (powdered) 9.57 9.57 9.57 9.57 2.81 Totalsolids 638.0 638.0 638.0 638.0 187.0 Liquid Formulations (mg/mL)Lisinopril dihydrate^(b) 1.09 1.09 1.09 1.09 1.09 Mannitol 50.33 50.6850.96 50.62 Xylitol 50.33 Citric acid, anhydrous 4.52 5.52 4.01 3.034.52 Sodium citrate, 6.83 5.48 7.51 8.83 6.83 anhydrous Potassiumsorbate 1.00 1.00 Sodium benzoate 1.00 1.00 1.00 Methylparaben sodium1.15 1.15 0.35 0.35 1.15 Sucralose 0.75 0.75 0.75 0.75 0.75 Grape flavor(powdered) 1.00 1.00 1.00 1.00 1.00 Purified water qs qs qs qs qsMeasured pH 4.7 4.3 4.8 5.2 4.7 ^(a)= contained ~8.4% water of hydrationto yield 1.0 mg/mL lisinopril upon constitution with water qs =sufficient quantity ^(b)= equivalent to 1 mg/mL lisinopril

The results of the HPLC analysis for the diketopiperazine andhydrolysate degradants in the samples are provided in Table B-2.

TABLE B-2 Degradant Content After Storage (% w/w of lisinopril) StorageFormulation ° C. Weeks B1 B2 B3 B4 B5 Powder FormulationsDiketopiperazine 19-23 0 <0.05 <0.05 <0.05 <0.05 <0.05 4 <0.05 0.05<0.05 <0.05 <0.05 8 0.05 0.06 0.05 0.05 0.07 12 0.07 0.07 <0.05 <0.05 400 <0.05 <0.05 <0.05 <0.05 <0.05 4 0.05 0.05 0.05 <0.05 0.06 8 0.07 0.070.06 0.05 0.09 12 0.10 0.10 0.09 0.07 Lisinopril 19-23 0 0.03 <0.05<0.05 <0.05 <0.05 hydrolysate 4 0.04 <0.05 <0.05 <0.05 0.05 8 0.05 0.05<0.05 <0.05 0.05 12 0.05 0.05 0.05 <0.05 40 0 0.03 <0.05 <0.05 <0.05<0.05 4 0.04 <0.05 <0.05 <0.05 0.05 8 0.05 0.05 <0.05 0.05 0.05 12 0.040.05 0.06 0.05 Liquid Formulations Diketopiperazine 19-23 0 0.05 0.050.06 <0.05 <0.05 4 0.06 0.09 0.06 <0.05 0.07 8 0.09 0.13 0.07 0.05 0.1012 0.12 0.18 0.12 0.11 40 0 0.05 0.05 0.06 <0.05 <0.05 4 0.23 0.46 0.190.11 0.23 8 0.42 0.87 0.35 0.15 0.46 12 0.67 1.40 0.59 0.27 Lisinopril19-23 0 <0.05 <0.05 <0.05 <0.05 <0.05 hydrolysate 4 <0.05 <0.05 0.05<0.05 0.05 8 0.05 0.05 0.05 0.05 0.05 12 0.05 0.05 0.05 0.06 40 0 <0.05<0.05 <0.05 <0.05 <0.05 4 0.08 0.08 0.10 0.07 0.13 8 0.15 0.16 0.15 0.140.17 12 0.17 0.19 0.20 0.16

Additionally the parabens also reacted with the sugar alcohols (xylitoland mannitol) to create new transesterification degradants.

Example C: Stability of Powder and Solution Formulations of Lisinoprilwith Alternate Sweeteners

Powder formulations were prepared according to Table C-1. All componentsin each formulation except mannitol or xylitol were mixed in a mortarand pestle then the mannitol or xylitol was added to the mortar inincrements with mixing to achieve geometric dilution. The final blendwas transferred to a 2.5 L polypropylene screw capped bottle and thebottle was mixed by inversion in a Turbula mixer for 10 minutes.Aliquots (2.4 g) of each formulation were placed into opaque highdensity polyethylene bottles. The bottles were screw-capped and placedinto storage at room temperature (19-23° C.) and at 40° C.±2° C. Oneliter of solution formulation was prepared for each formulation byadding 60.0 grams of powdered formulation C2 or C3, or 160 g of powderedformula C1 to one liter volumetric flasks and adding about 500 mL water.The powder was dissolved with mixing then the contents of the flaskswere brought to 1 L with additional water. Forty milliliter aliquots ofeach formulation were placed into HDPE bottles. The bottles werescrew-capped and placed into storage at room temperature (19-23° C.) andat 40° C.±2° C.

At various times, bottles were removed from the storage condition andanalyzed. The powder bottles were constituted with purified water toyield a final volume in each bottle of 40 mL.

TABLE C-1 Formulation of Lisinopril Formulations C1 C2 C3 PowderFormulations (grams) Lisinopril dihydrate^(a) 2.87 2.87 2.87 Xylitol408.1 138.34 Mannitol 136.22 Citric acid, anhydrous 2.32 2.32 2.32Sodium citrate, anhydrous 3.70 3.70 3.70 Sodium benzoate 2.64 2.64 2.64Sodium saccharin 5.94 Sucralose (as Rebalance X60) 7.92 Grape flavor(powdered) 2.64 2.64 2.64 Total solids 422.32 158.45 158.32 LiquidFormulations (mg/mL) Lisinopril dihydrate^(b) 1.09 1.09 1.09 Xylitol154.60 52.4 Mannitol 51.60 Citric acid, anhydrous 0.88 0.88 0.88 Sodiumcitrate, anhydrous 1.40 1.40 1.40 Sodium benzoate 1.00 1.00 1.00 Sodiumsaccharin 2.25 Sucralose (as Rebalance X60) 3.00 Grape flavor (powdered)1.00 1.00 1.00 Purified water qs qs qs Measured pH 4.8 4.8 4.8 ^(a)=contained ~8.4% water. Yields 1.0 mg/mL lisinopril upon constitutionwith water qs = sufficient quantity ^(b)= equivalent to 1 mg/mLlisinopril

The results for pH and the HPLC analysis for degradants in the samplesare provided in Table C-2.

TABLE C-2 Degradant Content After Storage (% w/w of Lisinopril) StorageFormulation ° C. weeks C1 C2* C3 Powder Formulations Diketopiperazine19-23 0 0.05 0.06 0.05 4 0.05 0.10 <0.05 8 0.05 0.12 <0.05 12 0.06 0.13<0.05 26 0.08 0.15 0.05 40 0 0.05 0.06 0.05 4 0.12 0.23 0.08 8 0.19 0.400.12 12 0.21 0.49 0.11 26 0.27 0.66 0.16 Lisinopril 19-23 0 0.06 0.05hydrolysate 4 0.05 0.05 8 <0.05 0.05 12 <0.05 <0.05 26 0.05 0.05 40 00.06 0.05 4 0.05 0.05 8 0.05 0.05 12 0.05 0.05 26 0.05 0.05 LiquidFormulations Diketopiperazine 19-23 0 <0.05 0.05 0.05 4 0.05 0.08 0.06 80.05 0.11 0.06 12 0.06 0.11 0.06 26 0.10 0.14 0.10 40 0 <0.05 0.05 0.054 0.16 0.20 0.17 8 0.30 0.34 0.30 12 0.45 0.49 0.45 26 0.87 0.90 0.83Lisinopril 19-23 0 0.05 0.05 hydrolysate 4 <0.05 0.05 8 0.05 0.05 120.05 0.05 26 0.06 0.06 40 0 0.05 0.05 4 0.08 0.09 8 0.12 0.13 12 0.190.19 26 0.36 0.36 *Hydrolysate could not be quantitated in the presenceof saccharin

Example D: Antimicrobial Effectiveness Testing at pH 4.8

Lisinopril formulations were prepared containing differing amounts ofthe antimicrobial preservative, sodium benzoate. The formulations werethen tested for antimicrobial effectiveness (AET) according to theprocedures in the 2014 United States Pharmacopeia 37, Chapter <51> forcategory 3 products. The formulation of the formulations and the AETresults are included in Table D-1.

TABLE D-1 Formulation and AET Testing Results Formulation D1 D2 D3 D4 D5Formulation (mg/mL) Lisinopril dihydrate^(a) 1.089 1.089 1.089 1.0891.089 Xylitol 155 155 155 155 155 Citric acid anhydrous 0.88 0.88 0.880.88 0.88 Sodium citrate anhydrous 1.40 1.40 1.40 1.40 1.40 Sodiumbenzoate 1.00 0.80 0.60 0.40 0.20 Grape Flavor 1.00 1.00 1.00 1.00 1.00Water qs qs qs qs qs HCl/NaOH as needed to achieve pH Measured pH 4.84.8 4.8 4.8 4.8 AET Results USP <51> Pass Pass Pass Fail Fail ^(a)=equivalent to 1 mg/mL lisinopril

Example E: Antimicrobial Effectiveness Testing at pH 5.0 and 5.1

Formulations were prepared containing differing amounts of theantimicrobial preservative, sodium benzoate and at pH values of 5.0 or5.1. The formulations were then tested for antimicrobial effectiveness(AET) according to the procedures in the 2015 United States Pharmacopeia38, Chapter <51> for category 3 products. The formulation of theformulations and the AET results are included in Table E-1.

TABLE E-1 Formulation and AET Testing Results Formulation E1 E2 E3 E4 E5E6 Formulation (mg/mL) Lisinopril dihydrate^(a) 1.089 1.089 1.089 1.0891.089 1.089 Xylitol 150.0 150.0 150.0 150.0 150.0 150.0 Citric acidanhydrous 0.86 0.86 0.86 0.86 0.86 0.86 Sodium citrate anhydrous 1.431.43 1.43 1.43 1.43 1.43 Sodium benzoate 0.80 0.76 0.72 0.68 0.64 0.72Water qs qs qs qs qs qs HCl/NaOH as needed to achieve pH Measured pH 5.05.0 5.0 5.0 5.0 5.1 AET Results USP <51> Pass Pass Pass Pass Pass Pass^(a)= equivalent to 1 mg/mL lisinopril

Example F: Stability of Solution Formulations of Lisinopril

Solution formulations were prepared according to Table F-1. Thecomponents were dissolved in about 80% of the final volume of water thenadditional water was added to bring the solution to final volume. The pHwas adjusted to the target pH with hydrochloric acid or sodium hydroxideThe solutions were dispensed into HDPE bottles, 40 mL of formulationsF1-F6 into 75 mL bottles, and 150 mL of formulation F7 into 150 mLbottles. The bottles were screw-capped and placed into controlledcondition storage at 5° C.±3° C., room temperature (19-23° C.) and at40° C.±2° C. At various times, bottles were removed from the storagecondition and analyzed. The results are shown in Table F-2.

TABLE F-1 Formulation (mg/mL) of Lisinopril Ready to Use LiquidFormulations Formulation F1 F2 F3 F4 F5 F6 F7 Lisinopril dihydrate^(a)1.09 1.09 1.09 1.09 1.09 1.09 1.09 Xylitol 150.0 150.0 150.0 100.0 150.0Citric acid anhydrous 1.92 1.92 1.92 1.92 1.92 1.92 0.86 Sodium citrateanhydrous 1.44 Sodium benzoate 0.80 0.80 0.80 0.80 Methylparaben sodium1.72 1.72 1.72 Propylparaben sodium 0.17 0.17 0.17 Glycerin 10.0Saccharin sodium 2.00 Sucralose USP 2.00 2.00 Water qs 1 mL qs 1 mL qs 1mL qs 1 mL qs 1 mL qs 1 mL qs 1 mL HCl/NaOH as needed to achieve pHTarget pH 4.8 4.8 4.8 5.2 5.2 5.2 5.0 ^(a)= equivalent to 1 mg/mLlisinopril

TABLE F-2 Degradant Content After Storage (% w/w of Lisinopril) StorageFormulation ° C. weeks F1 F2 F3 F4 F5 F6* F7 Lisinopril Diketopiperazine19-23 0 <0.05 0.05 0.05 0.05 0.06 0.05 <0.05 4 0.05 0.05 0.05 <0.05<0.05 0.07 <0.05 8 0.07 0.06 0.06 <0.05 <0.05 0.08 0.05 12 0.07 0.070.07 0.06 0.06 0.06 0.05 26 0.12 0.12 0.11 0.09 0.08 0.09 0.07 52 0.170.17 0.16 0.12 0.09 0.11 40 0 <0.05 0.05 0.05 0.05 0.06 0.05 <0.05 40.20 0.21 0.20 0.10 0.10 0.12 0.14 8 0.39 0.35 0.33 0.18 0.14 0.18 0.2712 0.51 0.49 0.45 0.25 0.22 0.23 0.36 26 1.13 1.11 1.04 0.56 0.49 0.540.71 52 1.93 1.89 1.72 0.90 0.83 0.89 Lisinopril Hydrolysate 19-23 00.05 <0.05 0.05 0.06 <0.05 0.05 4 0.05 0.05 0.05 0.06 0.06 0.05 8 0.050.05 0.06 0.05 0.05 <0.05 12 0.05 0.05 0.05 0.04 0.05 <0.05 26 0.07 0.070.07 0.06 0.07 0.05 52 0.08 0.08 0.08 0.06 0.08 40 0 0.05 <0.05 0.050.06 <0.05 0.05 4 0.11 0.11 0.11 0.08 0.10 0.11 8 0.17 0.16 0.16 0.110.14 0.13 12 0.18 0.18 0.18 0.12 0.17 0.18 26 0.45 0.46 0.49 0.31 0.440.36 52 0.87 0.89 0.91 0.62 0.84 *Hydrolysate could not be quantitatedin the presence of saccharin

Example G: Lisinopril Formulation at Higher pH

A solution formulation was prepared at pH 8.0 according to Table G-1.The components were dissolved in about 80% of the final volume of waterthen additional water was added to bring the solution to final volume.The pH was adjusted to the target pH with hydrochloric acid or sodiumhydroxide.

TABLE G-1 Formulation of Lisinopril Ready to Use Liquid Formulation atHigher pH Component mg/mL Lisinopril dihydrate^(a) 1.09 Monobasic sodiumphosphate anhydrous 2.40 Methylparaben sodium 1.72 Propylparaben sodium 0.225 Sucralose USP 0.70 Water qs HCl/NaOH as needed to achieve pHTarget pH 8.0  ^(a)= equivalent to 1 mg/mL lisinopril

Example H: Lisinopril Formulation Containing Less Sucralose

A solution formulation was prepared according to Table H-1. Thecomponents were dissolved in about 80% of the final volume of water thenadditional water was added to bring the solution to final volume. The pHwas adjusted to the target pH with hydrochloric acid or sodiumhydroxide.

TABLE H-1 Formulation of Lisinopril Ready to Use Liquid Formulation Withless Sucralose Component mg/mL Lisinopril dihydrate^(a) 1.09 Citric acidanhydrous 0.86 Sodium citrate anhydrous 1.44 Sodium benzoate 0.80Sucralose USP 0.70 Water qs HCl/NaOH as needed to achieve pH pH 4.9 ^(a)= equivalent to 1 mg/mL lisinopril

Example I: Clinical Trial: Bioavailability Study of 10 mg LisinoprilOral Solution Vs. Zestril 10 mg Tablets Under Fasted Conditions

The objective of this open-label, randomized, two period, two treatmentcrossover study was to compare the oral bioavailability of a testformulation of 10 mL of lisinopril oral solution, 1 mg/Ml (formulationF-7), to an equivalent oral dose of the commercially availablecomparator product, Zestril® lisinopril 10 mg tablet, when administeredunder fasted conditions in healthy adults.

Study design: Fifty-six healthy adult subjects received a single 10 mLdose of lisinopril oral solution, 1 mg/mL, formulation F-7 (TreatmentA), in one period and a separate single dose of Zestril 10 mg tablet(Treatment B) in another period. Screening assessments were performed bythe investigator or designee within 28 days prior to study start. Eachtreatment was administered after an overnight fast of at least 10 hours.Treatment A was administered via a 10 mL oral dosing syringe andfollowed with 240 mL of room temperature tap water. Treatment B wasadministered with 240 mL of room temperature tap water. The subjectsfasted for 4 hours after dosing. Except for the 240 mL of roomtemperature water provided with the dose, no water was consumed for 1hour prior through 1 hour postdose. Each drug administration wasseparated by a washout period of at least 7 days.

During each study period, meals were the same and scheduled atapproximately the same times relative to dose. In addition, during eachperiod, blood samples were obtained prior to and following each dose atselected times through 96 hours postdose. Pharmacokinetic samples wereanalyzed for lisinopril using a validated analytical method; appropriatepharmacokinetic parameters were calculated for each formulation usingnon-compartmental methods. Blood was also drawn and urine collected forclinical laboratory testing at screening and at the end of the study.

Statistical Methods: The concentration-time data were analyzed usingnoncompartmental methods in Phoenix™ WinNonlin® (Version 6.3, PharsightCorporation). Concentration-time data that were below the limit ofquantitation (BLQ) were treated as zero in the data summarization anddescriptive statistics. In the pharmacokinetic analysis, BLQconcentrations were treated as zero from time-zero up to the time atwhich the first quantifiable concentration was observed; embedded and/orterminal BLQ concentrations were treated as “missing”. Actual sampletimes were used for all pharmacokinetic and statistical analyses.Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-testprocedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf). The 90% confidence interval for the ratio ofthe geometric means (Test/Reference) was calculated. Bioequivalence wasdeclared if the lower and upper confidence intervals of thelog-transformed parameters were within 80% to 125%.

Results: Based on the geometric mean ratios of lisinopril AUCs(Test/Reference for AUC_(last) and AUC_(inf)), the bioavailability ofthe test formulation relative to the reference product was approximately94% to 95%. The geometric mean ratio of lisinopril C_(max) was 94.11%.The 90% confidence intervals about the geometric mean ratios(Test/Reference) of lisinopril C_(max) and AUCs were within the accepted80% to 125% range, indicating no significant difference.

Example J: Clinical Trial: Bioavailability Study of 10 mg LisinoprilOral Solution Vs. Zestril 10 mg Tablets Under Fed Conditions

This study was conduct the same as in example G, with the exceptionsthat only 52 subjects were analyzed for pharmacokinetic parameters, andthe dose administration followed a 10-hour overnight fast, followed bythe ingestion of a Food and Drug Administration standard high-calorie,high-fat breakfast meal.

Results: Based on the geometric mean ratios of lisinopril AUCs(Test/Reference for AUC_(last) and AUC_(inf)), the bioavailability ofthe test formulation relative to the reference product was approximately99% to 101%. The geometric mean ratio of lisinopril C_(max) was 99.45%.The 90% confidence intervals about the geometric mean ratios(Test/Reference) of lisinopril C_(max) and AUCs were within the accepted80% to 125% range, indicating no significant difference.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A stable oral liquid formulation, comprising: (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof; (ii) a sweetener selected from the group consisting ofxylitol, mannitol, sucralose, saccharin, and pharmaceutically acceptablesalts thereof; (iii) a buffer comprising an amino acid; (iv) apreservative selected from the group consisting of sodium benzoate,benzoic acid, sorbic acid, methylparaben, propylparaben, andpharmaceutically acceptable salts thereof; and (v) water; wherein theformulation is stable at about 25±5° C. for at least 6 months.
 2. Theformulation of claim 1, wherein the lisinopril is lisinopril dihydrate.3. The formulation of claim 1, wherein the pH of the formulation isbetween about 4 and about 5.2.
 4. The formulation of claim 1, whereinthe pH of the formulation is higher than
 4. 5. The formulation of claim1, wherein the formulation is stable at about 25±5° C. for at least 18months.
 6. The formulation of claim 1, wherein the formulation is stableat about 25±5° C. for at least 24 months.
 7. The formulation of claim 1,wherein the amino acid is lisinopril.
 8. The formulation of claim 1,wherein the buffer comprises an acid salt of an amino acid.
 9. Theformulation of claim 1, wherein the buffer comprises an alkali salt ofan amino acid.
 10. The formulation of claim 1, wherein the sweetener isxylitol, sucralose, or saccharin.
 11. The formulation of claim 10,wherein the xylitol is present in the formulation at about 140 mg/ml toabout 160 mg/ml.
 12. The formulation of claim 10, wherein the xylitol ispresent in the formulation at about 150 mg/ml.
 13. The formulation ofclaim 10, wherein the sucralose is present in the formulation at about0.5 mg/ml to about 3 mg/ml.
 14. The formulation of claim 10, wherein thesucralose is present in the formulation at about 0.7 mg/ml.
 15. Theformulation of claim 1, wherein the preservative is present in theformulation at about 0.1 mg/ml to about 2 mg/ml.
 16. The formulation ofclaim 1, wherein the preservative is present in the formulation at about0.8 mg/ml.
 17. A stable oral liquid formulation, consisting of: (i)about 1 mg/ml lisinopril or a pharmaceutically acceptable salt orsolvate thereof; (ii) about 150 mg/ml of a sweetener, wherein thesweetener is xylitol, mannitol, sucralose, saccharin, a pharmaceuticallyacceptable salt thereof, or a combination thereof; (iii) a buffercomprising an amino acid; (iv) about 0.8 mg/ml of a preservative,wherein the preservative is sodium benzoate, benzoic acid, sorbic acid,methylparaben, propylparaben, a pharmaceutically acceptable saltsthereof, or a combination thereof; and (v) water; wherein the pH of theformulation is between about 4 and about 5; and wherein the formulationis stable at about 25±5° C. for at least 6 months.
 18. The formulationof claim 17, wherein the preservative is sodium benzoate.
 19. Theformulation of claim 17, wherein the sweetener is xylitol.
 20. Theformulation of claim 17, wherein the amino acid is lisinopril.